This work was supported by SNF grants PPOOA-_119204 and PPOOP3_144918 to S.W.R. We thank E. Palmer and B.T.H. Hausmann for mice and technical expertise.

In diesem Video-Veröffentlichung und Protokoll wurden alle Tier Verfahren in Übereinstimmung mit der von der Kantonsbehörde Basel-Stadt, Schweiz zugelassenen Tier Protokoll durchgeführt. Führen Sie alle in sterilen Bedingungen, soweit möglich. 1. Vorbereitung der Chirurgie <ol><li> Autoklav alle chirurgischen Instrumenten und Gaze vor dem Gebrauch. </li><li> Erhitzen Sie die warmen Kissen und organisieren chirurgische Instrumente auf dem Tisch (Table of Materialien / Methoden). </li><li> Öffnen Sie die Fingerleiste Bandagen. Vaseline auf die Wundauflage mit einem Wattestäbchen (sicherstellen, dass die Gaze vollständig bedeckt ist). </li><li> Wiegen Sie die Mäuse und verwalten Analgesie Buprenorphin 0,05 mg / kg Körpergewicht. Hinweis: dies wird Analgesie unmittelbar nach der Transplantation bieten. </li></ol> 2. Vorbereitung der Schwanzhaut für Transplantation <ol><li> Euthanize Spendermäusen (zB IA BM12) pro CO 2-Erstickung und disinfect die Schwänze mit Desinfektionslösung vor Exzision. </li><li> Positionieren Sie den Schwanz mit dem schwarzen Streifen unten auf eine saubere Plastikbrett und schneiden Sie es in Längsrichtung über die Mittellinie, so dass eine oberflächliche Inzision, die nur die Hautschicht. </li><li> Ziehen Sie die Haut vom Schwanz mit Greifzange. </li><li> Setzen Sie den Schwanz-Haut in einer 10 cm Zellkulturschale mit 10 ml HBSS gefüllt. </li></ol> 3. Chirurgisches Vorgehen <ol><li> Betäuben Empfängermäuse (beispielsweise C57BL / 6) durch Inhalation einer 3% Isofluran Lösung in einem transparenten Induktionsfeld. Hinweis: Es dauert 3-5 min für die Maus, um chirurgische Anästhesie-Ebene zu erreichen. Verwenden Tierarzt Salbe auf die Augen zu Trockenheit während der Narkose zu vermeiden. </li><li> Legen Sie die Maus auf den warmen Pad und gelten 1,5% Isofluran über eine Mundmaske und Esel jedes Tier Reflex Zehen Kneifen. </li><li> Rasieren Sie die dorsale Seite der Empfängermäuse (zB C57BL / 6) und entfernen verunreinigende Haare mit einem trockenen Gaze swab. </li><li> Desinfizieren Sie rasiert Transplantation Website mit aseptischen Lösung. </li><li> Klemmen Sie die Haut mit einer Pinzette in der Mitte / rechts Seite des Rückens und einer gebogenen Schere verwenden, um eine Runde Schnitt von etwa 1 x 0,6 cm zu machen. </li><li> Wenn Blutungen auftreten, dann reinigen Sie die Wunde mit einem sterilen Wattestäbchen. </li><li> Bewerten Sie die Größe des Einschnitts und schneiden eine Transplantation von der geschätzten Größe von der Schwanzhaut mit dem Skalpell. </li><li> Schneiden Sie die Ecke der Transplantation runden. </li><li> Laden Sie die Transplantation auf dem Skalpell, trockenen Überschuss von HBSS auf einem sterilen Wattestäbchen und legen Sie sie in das Transplantat Bett der Empfängermaus. </li><li> Vermeiden Sie Überlagerung von Spender und Empfänger Haut und wenden Gewebekleber auf die Kontaktzone ausschließlich. </li><li> Tragen Sie eine Putz ohne Falten rund um die Maus Taille. </li><li> Kleber nicht-elastische Binde, das Pflaster auf die Maus zu beheben (3 mm verschoben). </li><li> Einzuschneiden mit der Schere etwa 3 mm im oberen ventralen Stelle der Bandage. Hinweis: Dies ist zu vermeiden, trapping von der Maus die Zähne während der Erholungsphase. </li><li> Entfernen Sie die Narkose-Mund-Maske und halten die transplantierten Mäusen auf dem Heizkissen bis wach. </li><li> Zurück transplantierten Mäusen in ihre Käfige nur bei vollständig erholt und beurteilen ihre Mobilität zu gewährleisten, dass der Verband nicht zu eng. </li><li> Sterilisieren Sie alle chirurgischen Instrumente mit 70% Ethanol, bevor mit der nächsten Operation fortfahren. </li></ol> 4. Post-operative Betreuung <ol><li> Hinzufügen Paracetamol enthaltenden Sirup zum Trinkwasser (4 mg / ml) und zu verwalten, für 7 Tage. </li><li> Zurück Maus an den Tierraum, sobald sie sich erholt hat. </li><li> Mäuse auf klinische Anzeichen wie Depressionen oder andere Verhaltensänderungen (Essen oder Immobilität), abnorme Erscheinung (mangelnde Pflege) oder Körperhaltung (Piloerektion oder gekrümmte Haltung) für die Zeit, die Binde ist vorhanden (1 Woche) genau beobachten. </li></ol> 5. Bandage Removal (6-7 Tage nach der Transplantation) <ol><li> Anesthetize Mäuse durch Inhalation einer 3% Isofluoran Lösung in einem transparenten Induktionsfeld (siehe oben). </li><li> Schneiden Verband und Gips mit Arterie Schere und sorgfältig zu entfernen. Hinweis: Vermeiden Sie Strecken des Transplantations Ort. </li><li> Überwachen Sie den transplantierten Mäusen für die klinische Anzeichen (siehe 4.3) und Punkte für die Ablehnung von Hauttransplantaten (Tabelle 1). Hinweis: Das Transplantat Score-System nutzt die Vorteile der verschiedenen Haartypen auf den Schwanz-Haut im Vergleich zu der Rückenhaut. In drei Typen wird das Aussehen des Transplantates und seiner Ablehnung kategorisiert. Die allogene Haut (MHC II nicht übereinstimm, z. B., IA BM12) Transplantate von C57BL / 6 immunkompetenten Mäusen in der Regel innerhalb von 12 bis 15 Tage nach der Transplantation (eigene Daten und 15-20) abgelehnt. </li></ol>

<ol>
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The authors declare that they have no competing financial interests.

Hauttransplantation ist ein weit verbreitetes Verfahren zur Untersuchung Ablehnung und Toleranz abhängig von T-Zellen. Da die Haut Transplantationsmodell gegründet wurde, wurden mehrere Anpassungen und Änderungen angewandt. Bei dem beschriebenen Verfahren wird IA-BM12 Schwanz Hauttransplantation durchgeführt unter Verwendung von Narkosegas (Isofluran). Die Verwendung von Gas Narkose verringert die Zeit der Ausführung und Mäuse Erholung, die die Belastung der transplantierten Mäusen abnimmt. Das Verfahr...

Transplantation von soliden Organen wie Haut, Herz und Nieren ist inzwischen ein Standardverfahren in der medizinischen Praxis weltweit ein. Erfolgreich transplantierten Organen kann durch Aktivierung des Immunsystems des Empfängers, der die Haupt-Histokompatibilitäts-Antigene des Spenders erkennt zurückzuweisen. Daher transplantierten Patienten müssen die Behandlung mit Immunsuppressiva 2. Die allogene Hauttransplantation bei Mäusen wurde durch Medawar und Kollegen im Jahr 1955 gegründet und war hilfreich für die Identifizierung der Zielmoleküle später als Major Histocompatibility Complex (MHC) Klasse I und II beschrieben. Seitdem hat sich die Haut Transplantationsmodell kontinuierlich modifiziert und angepasst ist, um die Rolle der T-Zelluntergruppen und die Bedeutung von chemischen und biologischen Intervention bei der Unterdrückung der Abstoßung 2-4 studieren. Haut aus dem Ohr und Rumpf sind schwieriger herzustellen und sind anfälliger für Hypoxie und Nekrose als Schwanzhaut 5; jedochdas Transplantationsverfahren ist ähnlich. Neben der Überwachung der Schwanzhauttransplantaten ist einfach aufgrund der charakteristischen Haarstruktur der Haut. Dieser Artikel enthält eine detaillierte Prozedur für die MHC-Klasse-II-Fehlanpassung Schwanzhauttransplantation, die für die Untersuchung verschiedener Aspekte der CD4 + T-Zell-vermittelten Abstoßung und Toleranz bei Mäusen ermöglicht. Die natürliche Dreipunktmutation in der MHC-Klasse-II-Molekül IA b (genannt IA BM12) 6-9 ist ausreichend, um eine Abstoßung von Hauttransplantate in C57BL / 6 Mäusen 8 induzieren. Die IA BM12 Molekül aktiviert CD4 + T-Zellen mit verschiedenen αβ-T-Zellrezeptor (TCR)-Ketten von C57BL / 6 Mäusen, unter denen Vα2Vβ8-TCR-spezifische T-Zellen, um eine TcR-transgenen Maus 10 erzeugt identifiziert. Der adoptive Transfer von Vα2Vβ8-TCR-spezifische T-Zellen wurde verwendet, um eine Abstoßungsmodell in immundefizienten C57B etablierenL / 6 Rag2 - / - Mäuse mit IA BM12 Haut transplantiert. Genetische Unterschiede zwischen Spender und Empfänger beeinflussen das Ergebnis der Transplantat-Akzeptanz und Zurückweisung. Es gibt verschiedene Arten von Transplantationen: autologen Transplantationen sind vom Empfänger Individuum selbst; syngrafts und Allografts sind Transplantationen von genetisch identisch und genetisch nicht verwandten Individuen sind. Akzeptanz unterschiedlicher allogenen Organtransplantationen durch chemische und biologische Intervention bei Patienten und Mausmodellen 11,3,4 nachgewiesen. In einem grundlegenden Ansatz zeigte anti-CD3-Antikörper-behandelten C57BL / 6 Mäuse verlängerten Überlebenszeit von IA BM12 tail-Haut (unveröffentlichte Daten). Depletion von CD4 + und CD8 + T-Zellen vor der Transplantation in Empfängermäuse führte die Annahme der MHC-Klasse I und II nicht übereinstimm Transplantate (rev. 12). Interessanterweise Abstoßung von Hauttransplantaten, von der Anwesenheit von CD4 + </sup&gt; T-Zellen (rev. 12). In diesem Modell, auf bestimmte Interaktionen zwischen den verschiedenen Immunzellen durch Blockierung kostimulatorische Moleküle mit Antikörpern oder Unterdrückung der regulatorischen T-Zellen könnte Toleranz (unveröffentlichte Daten) zu induzieren. In der Tat, Sperrung sowohl CD40 und CD28 führte zu langfristigen Hauttransplantattoleranz 13,14. Schwanz-Hauttransplantation ist einfach durchzuführen und einfach zu überwachen, im Vergleich zur Transplantation anderer Organe. Darüber hinaus sind Schwanzhauttransplantate leicht herzustellen und sind weniger anfällig für Ischämie als andere Hautgewebe. Im Gegensatz zu injizierenden Anästhetika, die Verwendung von Narkosegas (Isofluran) während der Transplantation verkürzt sowohl die Verfahren und Empfänger Erholungszeit. Curling der Schwanzhaut-Transplantation, die unvollständig Wundheilung und Transplantat-Abstoßung führen kann, wird durch die Anwendung von Gewebekleber verhindert. Darüber hinaus wird die IA-BM12 Schwanz Hauttransplantation Modell aktiviert CD4 ausschließlich <sup&gt; + T-Zellen sowohl in der immunkompetenten und immungeschwächten Mäusen (aus dem gleichen genetischen Hintergrund) die Erleichterung der Interpretation der Ergebnisse. Dieses Protokoll beschreibt einen zuverlässigen, reproduzierbaren und leicht überwacht Maus-Modell, das für die chemische und biologische Eingriffe ermöglicht. Das Modell ist für die Untersuchung von Ablehnung und Toleranzinduktion von tail-Hauttransplantationen vorgesehen.

<table border="0" cellpadding="0" cellspacing="0" width="831">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Name of Material/ Equipment</td>
			<td style="width:183px;">Company</td>
			<td style="width:119px;">Catalog Number</td>
			<td style="width:231px;">Comments/Description</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Betadine Standard solution</td>
			<td>Mundipharma</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Cotton swab</td>
			<td style="width:183px;">Carl Roth GmbH</td>
			<td style="width:119px;">31025060</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Dafalgan , UPSA</td>
			<td>Bristol Myers Squibb SA</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Hansaplast Finger Strips</td>
			<td>Beierdorf AG</td>
			<td style="width:119px;">REF.76861</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Histoacryl Tissue adhesive</td>
			<td style="width:183px;">Braun</td>
			<td style="width:119px;">REF.1050052</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Leukotape classic , 2cm x 10 m</td>
			<td>BSN Medical SAS</td>
			<td>REF.02204-00</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">PBS, Phosphate-Buffered Saline, pH 7.4</td>
			<td style="width:183px;">Invitrogen</td>
			<td style="width:119px;">10010015</td>
			<td>GIBCO</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Sterile gauze, 5 x 5cm, 8ply</td>
			<td>MaiMed GmbH</td>
			<td>21010</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Surgical instruments&#160;</td>
			<td style="width:183px;">FST</td>
			<td style="width:119px;">11003-12</td>
			<td>Narrow pattern forceps,&#160;</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:299px;"></td>
			<td style="width:183px;"></td>
			<td style="width:119px;">14095-11</td>
			<td>Fine iris scissor curved,</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;"></td>
			<td style="width:183px;"></td>
			<td style="width:119px;">14094-11</td>
			<td>Fine iris scissor&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;"></td>
			<td style="width:183px;"></td>
			<td style="width:119px;">14010-15</td>
			<td>Mayo scissors,</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;"></td>
			<td style="width:183px;"></td>
			<td style="width:119px;">14080-11</td>
			<td>Artery scissors ball tip 11.5 cm&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;"></td>
			<td style="width:183px;"></td>
			<td style="width:119px;">11021-14</td>
			<td>Tissue forceps</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Surgical Blade No.20</td>
			<td style="width:183px;">Swann-Morton LTD</td>
			<td style="width:119px;">3006</td>
			<td>Carbon Steel</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Surgical blade Handles</td>
			<td style="width:183px;">Swann-Morton LTD</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Syringe, 1ml</td>
			<td style="width:183px;">ARTSANA</td>
			<td style="width:119px;"></td>
			<td>disposable</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Temgesic , Buprenorphine</td>
			<td style="width:183px;">ESSEX Chemie AG</td>
			<td style="width:119px;"></td>
			<td>0.3mg/ml</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Tissue Culture dishes 10 cm, 60.1 cm2</td>
			<td style="width:183px;">TPP</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Vaseline</td>
			<td style="width:183px;">Vifor SA</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:299px;">Warm pad</td>
			<td style="width:183px;">Solis</td>
			<td style="width:119px;"></td>
			<td>Type 223</td>
		</tr>
	</tbody>
</table>

transplantation of tail skin to study allogeneic cd4 t cell responses in mice

The study of T cell responses and their consequences during allo-antigen recognition requires a model that enables one to distinguish between donor and host T cells, to easily monitor the graft, and to adapt the system in order to answer different immunological questions. Medawar and colleagues established allogeneic tail-skin transplantation in mice in 1955. Since then, the skin transplantation model has been continuously modified and adapted to answer specific questions. The use of tail-skin renders this model easy to score for graft rejection, requires neither extensive preparation nor deep anesthesia, is applicable to animals of all genetic background, discourages ischemic necrosis, and permits chemical and biological intervention. 
In general, both CD4+ and CD8+ allogeneic T cells are responsible for the rejection of allografts since they recognize mismatched major histocompatibility antigens from different mouse strains. Several models have been described for activating allogeneic T cells in skin-transplanted mice. The identification of major histocompatibility complex (MHC) class I and II molecules in different mouse strains including C57BL/6 mice was an important step toward understanding and studying T cell-mediated alloresponses. In the tail-skin transplantation model described here, a three-point mutation (I-Abm12) in the antigen-presenting groove of the MHC-class II (I-Ab) molecule is sufficient to induce strong allogeneic CD4+ T cell activation in C57BL/6 mice. Skin grafts from I-Abm12 mice on C57BL/6 mice are rejected within 12-15 days, while syngeneic grafts are accepted for up to 100 days. The absence of T cells (CD3-/- and Rag2-/- mice) allows skin graft acceptance up to 100 days, which can be overcome by transferring 2 x 104 wild type or transgenic T cells. Adoptively transferred T cells proliferate and produce IFN-&#947; in I-Abm12-transplanted Rag2-/- mice.

In einem ersten Ansatz wurden C57BL / 6 Mäuse mit IA BM12 Allografts und IA b syngrafts transplantiert. Bandage nach Entfernung Transplantate offensichtlichen Anzeichen der Wundheilung ohne Schließung der Kontaktzone in C57BL / 6 Mäusen (Fig. 1A). Bandage nach Entfernung führte CD4 + T-Zell-vermittelte Entzündung zu dem Auftreten von Nekrosen (rote Punkte) und Ablehnung IA BM12 Allotransplantaten in C57BL / 6 Mäusen innerhalb von 13 Tagen nach der Transp...

Watch this Scientific Journal Video about Transplantation of Tail Skin to Study Allogeneic CD4 T Cell Responses in Mice at JoVE.com

Transplantation of Tail Skin to Study Allogeneic CD4 T Cell Responses in Mice

Tail-skin transplantation is a powerful model for studying T cell-dependent rejection and tolerance induction during allogeneic immune responses in mice. The advantages of this protocol are minor invasive surgery, and ease of monitoring with no need to sacrifice the recipient mouse.

Transplantation von Haut-Schwanz zu allogene CD4-T-Zellantworten in Mäusen untersucht

The study of T cell responses and their consequences during allo-antigen recognition requires a model that enables one to distinguish between donor and ...

transplantation-tail-skin-to-study-allogeneic-cd4-t-cell-responses

Research

JoVE Journal

Immunology and Infection

12.2K Aufrufe.  University of Basel and University Hospital Basel. Tail-skin transplantation is a powerful model for studying T cell-dependent rejection and tolerance induction during allogeneic immune responses in mice. The advantages of this protocol are minor invasive surgery, and ease of monitoring with no need to sacrifice the recipient mouse.

Serie: Transplantation of Tail Skin to Study Allogeneic CD4 T Cell Responses in Mice

Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant

Viral infections cause morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We and others have successfully generated and infused T-cells specific for Epstein Barr virus (EBV), cytomegalovirus (CMV) and Adenovirus (Adv) using monocytes and EBV-transformed lymphoblastoid cell (EBV-LCL) gene-modified with an adenovirus vector as antigen presenting cells (APCs). As few as 2x105/kg trivirus-specific cytotoxic T lymphocytes (CTL) proliferated by several logs after infusion and appeared to prevent and treat even severe viral disease resistant to other available therapies. The broader implementation of this encouraging approach is limited by high production costs, complexity of manufacture and the prolonged time (4-6 weeks for EBV-LCL generation, and 4-8 weeks for CTL manufacture &#x2013; total 10-14 weeks) for preparation. To overcome these limitations we have developed a new, GMP-compliant CTL production protocol. First, in place of adenovectors to stimulate T-cells we use dendritic cells (DCs) nucleofected with DNA plasmids encoding LMP2, EBNA1 and BZLF1 (EBV), Hexon and Penton (Adv), and pp65 and IE1 (CMV) as antigen-presenting cells. These APCs reactivate T cells specific for all the stimulating antigens. Second, culture of activated T-cells in the presence of IL-4 (1,000U/ml) and IL-7 (10ng/ml) increases and sustains the repertoire and frequency of specific T cells in our lines. Third, we have used a new, gas permeable culture device (G-Rex) that promotes the expansion and survival of large cell numbers after a single stimulation, thus removing the requirement for EBV-LCLs and reducing technician intervention. By implementing these changes we can now produce multispecific CTL targeting EBV, CMV, and Adv at a cost per 106 cells that is reduced by &gt;90%, and in just 10 days rather than 10 weeks using an approach that may be extended to additional protective viral antigens. Our FDA-approved approach should be of value for prophylactic and treatment applications for high risk allogeneic HSCT recipients.

A rapid, simple and cost-effective protocol for the generation of donor-derived multivirus-specific CTLs (rCTL) for infusion to allogeneic hematopoietic stem cell transplant (HSCT) recipients at risk of developing CMV, Adv or EBV infections. This manufacturing process is GMP-compliant and should ensure the broader implementation of T-cell immunotherapy beyond specialized centers.

Generierung von Multivirus-spezifischen T-Zellen zu verhindern / zu behandeln virale Infektionen nach allogenen hämatopoetischen Stammzelltransplantation

Viral infections cause morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We and others have successfully ...

Forschung

Immunologie und Infektion

Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells

The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes after 12 weeks of age and is the most extensively studied animal model of human Type 1 diabetes (T1D). Cell transfer studies in irradiated recipient mice have established that T cells are pivotal in T1D pathogenesis in this model. We describe herein a simple method to rapidly induce T1D by adoptive transfer of purified, primary CD4+ T cells from pre-diabetic NOD mice transgenic for the islet-specific T cell receptor (TCR) BDC2.5 into NOD.SCID recipient mice. The major advantages of this technique are that isolation and adoptive transfer of diabetogenic T cells can be completed within the same day, irradiation of the recipients is not required, and a high incidence of T1D is elicited within 2 weeks after T cell transfer. Thus, studies of pathogenesis and therapeutic interventions in T1D can proceed at a faster rate than with methods that rely on heterogenous T cell populations or clones derived from diabetic NOD mice.

We provide a reproducible method to induce type 1 diabetes (T1D) in mice within two weeks by the adoptive transfer of islet antigen-specific, primary CD4+ T cells.

Accelerated Typ 1 Diabetes Induktion in Mäusen durch adoptiven Transfer von CD4 + T diabetogene Cells

The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes after 12 weeks of age and is the most extensively studied animal model of ...

Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation

Regulatory T cells (Tregs) are essential to provide immune tolerance to self as well as to certain foreign antigens. Tregs can be generated from naive CD4 T cells in vitro with TCR- and co-stimulation in the presence of TGF&beta; and IL-2. This bears enormous potential for future therapies, however, the molecules and signaling pathways that control differentiation are largely unknown.
Primary T cells can be manipulated through ectopic gene expression, but common methods fail to target the most important naive state of the T cell prior to primary antigen recognition. Here, we provide a protocol to express ectopic genes in naive CD4 T cells in vitro before inducing Treg differentiation. It applies transduction with the replication-deficient adenovirus and explains its generation and production. The adenovirus can take up large inserts (up to 7 kb) and can be equipped with promoters to achieve high and transient overexpression in T cells. It effectively transduces naive mouse T cells if they express a transgenic Coxsackie adenovirus receptor (CAR). Importantly, after infection the T cells remain naive (CD44low, CD62Lhigh) and resting (CD25-, CD69-) and can be activated and differentiated into Tregs similar to non-infected cells. Thus, this method enables manipulation of CD4 T cell differentiation from its very beginning. It ensures that ectopic gene expression is already in place when early signaling events of the initial TCR stimulation induces cellular changes that eventually lead into Treg differentiation.

Adenoviral gene transfer into naive CD4 T cells with transgenic expression of the Coxsackie adenovirus receptor enables the molecular analysis of regulatory T cell differentiation in vitro.

Adenovirale Transduktion von Naive CD4 T-Zellen zu Treg Differenzierung Studieren

Regulatory T cells (Tregs) are essential to provide immune tolerance to self as well as to certain foreign antigens. Tregs can be generated from naive CD4 ...

Isolation and Th17 Differentiation of Na&iuml;ve CD4 T Lymphocytes

Th17 cells are a distinct subset of T cells that have been found to produce interleukin 17 (IL-17), and differ in function from the other T cell subsets including Th1, Th2, and regulatory T cells. Th17 cells have emerged as a central culprit in overzealous inflammatory immune responses associated with many autoimmune disorders. In this method we purify T lymphocytes from the spleen and lymph nodes of C57BL/6 mice, and stimulate purified CD4+ T cells under control and Th17-inducing environments. The Th17-inducing environment includes stimulation in the presence of anti-CD3 and anti-CD28 antibodies, IL-6, and TGF-&#946;. After incubation for at least 72 hours and for up to five days at 37 &#176;C, cells are subsequently analyzed for the capability to produce IL-17 through flow cytometry, qPCR, and ELISAs. Th17 differentiated CD4+CD25- T cells can be utilized to further elucidate the role that Th17 cells play in the onset and progression of autoimmunity and host defense. Moreover, Th17 differentiation of CD4+CD25- lymphocytes from distinct murine knockout/disease models can contribute to our understanding of cell fate plasticity.

Isolation and Th17 Differentiation of Na&amp;#239;ve CD4 T Lymphocytes

With effector functions distinct from other T cell subsets, Th17 cells have been centrally implicated in inflammatory autoimmunity. This in vitro Th17 differentiation protocol provides a means to determine whether na&#239;ve CD4+ T lymphocytes can differentiate into Th17 cells, and to further examine their role in autoimmunity and host response.

Isolierung und Differenzierung von Th17 Naive CD4-T-Lymphozyten

Th17 cells are a distinct subset of T cells that have been found to produce interleukin 17 (IL-17), and differ in function from the other T cell subsets ...

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice

There are many different animal models available for studying the pathogenesis of human inflammatory bowel diseases (IBD), each with its own advantages and disadvantages. We describe here an experimental colitis model that is initiated by adoptive transfer of syngeneic splenic CD4+CD45RBhigh T cells into T and B cell deficient recipient mice. The CD4+CD45RBhigh T cell population that largely consists of na&#239;ve effector cells is capable of inducing chronic intestinal inflammation, closely resembling key aspects of human IBD. This method can be manipulated to study aspects of disease onset and progression. Additionally it can be used to study the function of innate, adaptive, and regulatory immune cell populations, and the role of environmental exposures, i.e., the microbiota, in intestinal inflammation. In this article we illustrate the methodology for inducing colitis with a step-by-step protocol. This includes a video demonstration of key technical aspects required to successfully develop this murine model of experimental colitis for research purposes.

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice

Here, we present a protocol to induce colonic inflammation in mice by adoptive transfer of syngeneic CD4+CD45RBhigh T cells into T and B cell deficient recipients. Clinical and histopathological features mimic human inflammatory bowel diseases. This method allows the study of the initiation of colonic inflammation and progression of disease.

Die Induktion von Murine Darmentzündungen durch adoptiven Transfer von Effektor CD4<sup&gt; +</sup&gt; CD45RB<sup&gt; Hoch</sup&gt; T-Zellen in immundefizienten Mäusen

There are many different animal models available for studying the pathogenesis of human inflammatory bowel diseases (IBD), each with its own advantages ...

Mouse Na&#239;ve CD4+ T Cell Isolation and In vitro Differentiation into T Cell Subsets

Antigen inexperienced (na&#239;ve) CD4+ T cells undergo expansion and differentiation to effector subsets at the time of T cell receptor (TCR) recognition of cognate antigen presented on MHC class II. The cytokine signals present in the environment at the time of TCR activation are a major factor in determining the effector fate of a na&#239;ve CD4+ T cell. Although the cytokine environment during na&#239;ve T cell activation may be complex and involve both redundant and opposing signals in vivo, the addition of various cytokine combinations during naive CD4+ T cell activation in vitro can readily promote the establishment of effector T helper lineages with hallmark cytokine and transcription factor expression. Such differentiation experiments are commonly used as a first step for the evaluation of targets believed to promote or inhibit the development of certain CD4+ T helper subsets. The addition of mediators, such as signaling agonists, antagonists, or other cytokines, during the differentiation process can also be used to study the influence of a particular target on T cell differentiation. Here, we describe a basic protocol for the isolation of na&#239;ve T cells from mouse and the subsequent steps necessary for polarizing na&#239;ve cells to various T helper effector lineages in vitro.

Mouse Na&amp;#239;ve CD4+ T Cell Isolation and In vitro Differentiation into T Cell Subsets

Na&#239;ve CD4+ T cells polarize to various subsets depending on the environment at the time of activation. The differentiation of na&#239;ve CD4+ T cells to various effector subsets can be achieved in vitro through the addition of T cell receptor stimuli and specific cytokine signals.

Maus Naive CD4<sup&gt; +</sup&gt; T-Zell-Isolierung und<em&gt; In-vitro-</em&gt; Differenzierung in T-Zell-Populationen

Antigen inexperienced (na&#239;ve) CD4+ T cells undergo expansion and differentiation to effector subsets at the time of T cell receptor (TCR) recognition ...

Imaging CD4 T Cell Interstitial Migration in the Inflamed Dermis

The ability of CD4 T cells to carry out effector functions is dependent upon the rapid and efficient migration of these cells in inflamed peripheral tissues through an as-yet undefined mechanism. The application of multiphoton microscopy to the study of the immune system provides a tool to measure the dynamics of immune responses within intact tissues. Here we present a protocol for non-invasive intravital multiphoton imaging of CD4 T cells in the inflamed mouse ear dermis. Use of a custom imaging platform and a venous catheter allows for the visualization of CD4 T cell dynamics in the dermal interstitium, with the ability to interrogate these cells in real-time via the addition of blocking antibodies to key molecular components involved in motility. This system provides advantages over both in vitro models and surgically invasive imaging procedures. Understanding the pathways used by CD4 T cells for motility may ultimately provide insight into the basic function of CD4 T cells as well as the pathogenesis of both autoimmune diseases and pathology from chronic infections.

The mechanisms that govern the interstitial motility of CD4 effector T cells at sites of inflammation are relatively unknown. We present a non-invasive approach to visualize and manipulate in vitro-primed CD4 T cells in the inflamed ear dermis, allowing for study of the dynamic behavior of these cells in situ.

Imaging CD4 T-Zell-Interstitial Migration in den entzündeten Dermis

The ability of CD4 T cells to carry out effector functions is dependent upon the rapid and efficient migration of these cells in inflamed peripheral ...

In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients

The main concern in transplantation is to achieve specific tolerance through induction of regulatory cells. The understanding of tolerance mechanisms requires reliable models. Here, we describe models of tolerance to cardiac allograft in rat, induced by blockade of costimulation signals or by upregulation of immunoregulatory molecules through gene transfer. Each of these models allowed in vivo generation of regulatory cells such as regulatory T cells (Tregs), regulatory B cells (Bregs) or regulatory myeloid cells (RegMCs). In this manuscript, we describe two complementary protocols that have been used to identify and define in vitro and in vivo regulatory cell activity to determine their responsibility in tolerance induction and maintenance. First, an in vitro suppressive assay allowed rapid identification of cells with suppressive capacity on effector immune responses in a dose dependent manner, and can be used for further analysis such as cytokine measurement or cytotoxicity. Second, the adoptive transfer of cells from a tolerant treated recipient to a newly irradiated grafted recipient, highlighted the tolerogenic properties of these cells in controlling graft directed immune responses and/or converting new regulatory cells (termed infectious tolerance). These methods are not restricted to cells with known phenotypic markers and can be extended to any cell population. Furthermore, donor directed allospecificity of regulatory cells (an important goal in the field) can be assessed by using third party donor cells or graft either in vitro or in vivo. Finally, to determine the specific tolerogenic capacity of these regulatory cells, we provide protocols to assess the humoral anti-donor antibody responses and the capacity of the recipient to develop humoral responses against new or former known antigens. The models of tolerance described can be used to further characterize regulatory cells, to identify new biomarkers, and immunoregulatory molecules, and are adaptable to other transplantation models or autoimmune diseases in rodent or human.

In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients

Here, we present a protocol to induce tolerance in transplantation, and assess in vitro and in vivo the suppressive capacity of distinct cell subsets from the recipient and the immune status of the recipient toward donor or exogenous antigens.

In Vitro und In Vivo Beurteilung der T, B und myeloische Zellen Suppressive Aktivität und humorale Reaktionen von Transplantationspatienten

The main concern in transplantation is to achieve specific tolerance through induction of regulatory cells. The understanding of tolerance mechanisms ...

A Suction Blister Protocol to Study Human T-cell Recall Responses In Vivo

Cutaneous antigen-recall models allow for studies of human memory responses in vivo. When combined with skin suction blister (SB) induction, this model offers accessibility to rare populations of antigen-specific T-cells representative of the cellular memory response as well as the cytokine microenvironment in situ.
This report describes the practical procedure of a cutaneous recall, an SB induction, and a harvest of antigen-specific T-cells. To exemplify the method, the tuberculin skin test is used for antigenic recall in individuals who, prior to this study, underwent a Bacillus Calmette-Gu&#233;rin vaccination against an infection with Mycobacterium tuberculosis. Finally, examples of multiplex and flow cytometric analyses of SB specimens are provided, illustrating high fractions of antigen-specific polyfunctional CD4+ T-cells available by this sampling method compared with cells isolated from the blood.
The method described here is safe and minimally invasive, provides a unique opportunity to study both innate and adaptive immune responses in vivo, and may be beneficial to a broad community of researchers working with cell-mediated immunity and human memory responses, in the context of vaccine development.

A Suction Blister Protocol to Study Human T-cell Recall Responses In Vivo

Here, we provide a demonstration of the suction blister cutaneous recall model. The model allows a simple access to study human in vivo adaptive immune responses, for instance in the context of vaccine development.

Ein Saug Blister-Protokoll, menschliche T-Zelle Recall Antworten In Vivo zu studieren

Cutaneous antigen-recall models allow for studies of human memory responses in vivo. When combined with skin suction blister (SB) induction, this model ...

Evaluation of Zika Virus-specific T-cell Responses in Immunoprivileged Organs of Infected Ifnar1-/- Mice

The Zika virus (ZIKV) can induce inflammation in immunoprivileged organs (e.g., the brain and testis), leading to the Guillain-Barr&#233; syndrome and damaging the testes. During an infection with the ZIKV, immune cells have been shown to infiltrate into the tissues. However, the cellular mechanisms that define the protection and/or immunopathogenesis of these immune cells during a ZIKV infection are still largely unknown. Herein, we describe methods to evaluate the virus-specific T-cell functionality in these immunoprivileged organs of ZIKV-infected mice. These methods include a) a ZIKV infection and vaccine inoculation in Ifnar1-/- mice; b) histopathology, immunofluorescence, and immunohistochemistry assays to detect the virus infection and inflammation in the brain, testes, and spleen; c) the preparation of a tetramer of ZIKV-derived T-cell epitopes; d) the detection of ZIKV-specific T cells in the monocytes isolated from the brain, testes, and spleen. Using these approaches, it is possible to detect the antigen-specific T cells that have infiltrated into the immunoprivileged organs and to evaluate the functions of these T cells during the infection: potential immune protection via virus clearance and/or immunopathogenesis to exacerbate the inflammation. These findings may also help to clarify the contribution of T cells induced by the immunization against ZIKV.

Evaluation of Zika Virus-specific T-cell Responses in Immunoprivileged Organs of Infected Ifnar1-/- Mice

A protocol to evaluate antigen-specific T-cell responses in the immunoprivileged organs of the Ifnar1-/- murine model for the Zika virus (ZIKV) infection is described. This method is pivotal for investigating the cellular mechanisms of the protection and immunopathogenesis of ZIKV vaccines and is also valuable for their efficacy evaluation.

Bewertung der Zika-Virus-spezifischen T-Zell-Reaktionen in Organe der Immunabwehr von infizierten Ifnar1- / - Mäusen

The Zika virus (ZIKV) can induce inflammation in immunoprivileged organs (e.g., the brain and testis), leading to the Guillain-Barr&#233; syndrome and ...