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Identification of Rare Antigen-Specific T Cells from Mouse Lungs with Peptide:Major Histocompatibility Complex Tetramers

The identification and characterization of antigen-specific T cells during health and disease remains a key to improving our understanding of immune ...

Massachusetts General Hospital

Boston Children's Hospital

Harvard Medical School

Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.

Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

CD4 T cells are central to long-term immunity against viruses through the functions of T helper 1 (T1) and T follicular helper (T) cell subsets. To better understand the role of these subsets in coronavirus disease 2019 (COVID-19) immunity, we conducted a longitudinal study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4 T cell and antibody responses in convalescent individuals who seroconverted during the first wave of the pandemic in Boston, MA, USA, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4 T cells using peptide and major histocompatibility complex class II (pMHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most individuals compared with prepandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating T (cT) and T1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4 T cells responses in a subset of individuals with sustained anti-S antibody responses after viral clearance also revealed an increased proportion of memory cT cells. Our findings indicate that efficient early disease control also predicts favorable long-term adaptive immunity.

SARS-CoV-2 epitope-specific CD4 memory T cell responses across COVID-19 disease severity and antibody durability.

Acute kidney injury in patients receiving pembrolizumab combination therapy versus pembrolizumab monotherapy for advanced lung cancer.

Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration.

Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

Self-antigen-specific T cells are prevalent in the mature adaptive immune system but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow these T cells to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self-antigen under highly stimulatory conditions, we use peptide:major histocompatibility complex (MHC) class II tetramers to track the behavior of endogenous CD4 T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury. Acute injury results in the exclusive expansion of CD4 regulatory T cells (Tregs) that is dependent on self-antigen recognition and interleukin-2 (IL-2). Conversely, conventional CD4 T cells of the same self-antigen specificity remain unresponsive even following Treg ablation. Thus, the self-antigen-specific CD4 T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.

Article	Year
Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study. Journal of the American Society of Nephrology : JASN\| PubMed ID: 31896554	2020
Acute kidney injury in patients treated with immune checkpoint inhibitors. Journal for immunotherapy of cancer\| PubMed ID: 34625513	2021
SARS-CoV-2 epitope-specific CD4 memory T cell responses across COVID-19 disease severity and antibody durability. Science immunology\| PubMed ID: 35857584	2022
Acute kidney injury in patients receiving pembrolizumab combination therapy versus pembrolizumab monotherapy for advanced lung cancer. Kidney international\| PubMed ID: 35964800	2022
Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI. Journal for immunotherapy of cancer\| PubMed ID: 36137651	2022
Lung injury induces a polarized immune response by self-antigen-specific CD4 Foxp3 regulatory T cells. Cell reports\| PubMed ID: 37471223	2023

Daniel S. Shin

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