Antibody-suppressor CD8+ T cells require IFN-γ and CD4+ T cells for optimal development and effector function
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Date
2021-05
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The Ohio State University
Abstract
Antibody-mediated rejection is a significant contributor to organ transplant failure. The Bumgardner Lab has recently discovered a novel subset of CD8+ T cells (CD8+ TAb-supp cells) that express CXCR5 and suppress transplant-specific antibody (alloantibody), which results in prolonged transplant survival in mouse models. To further understand these cells, we set out to investigate the requirements for CXCR5+CD8+ TAb-supp cell development. Previous reports suggest that IFN-γ cytokine may be critical for the development of CD8+ TAb-supp cells, and I further hypothesized that CD4+ T cells are also important for their development. To investigate these hypotheses, wild-type mice or mice lacking IFN-γ, IFN-γ receptor (IFN-γR), and/or CD4+ T cells were stimulated with allogeneic antigen. In some cohorts, naïve CD8+ T cells were adoptively transferred (AT) into stimulated mice. One week following stimulation, cells were isolated from the spleens of stimulated mice and analyzed for the CD8+ TAb-supp phenotype (CXCR5), activation (CD44), proliferation, and cytotoxic effector molecules. To date, we have found that the quantity of CXCR5+CD8+ T cells (wild-type, 13.5%) was downregulated in mice that lacked CD4+ T cells (6.8%; 2-fold) or IFN-γ (8.5%; 1.5-fold). While activation was not affected by IFN-γ or CD4+ T cells, proliferation of wild-type CXCR5+CD8+ T cells is dependent on host expression of IFN-γ (wild-type=33.5% versus IFN-γ KO=19.7%). In addition, the cytotoxic effector phenotype of activated CXCR5+CD8+ T cells is nearly abrogated when hosts are IFN-γ deficient (Lamp1: WT=70.0% versus IFN-γ KO=6.7%; FasL: WT=36.5% versus IFN-γ KO=6.7%).
To date, experiments using mutant CD8+ T cells adoptively transferred into wild-type hosts show no variance in CXCR5 expression, activation, or effector molecule expression. Thus, our current data, despite relatively small sample sizes, suggests a critical role for both host IFN-γ expression and CD4+ T cells in maximizing CXCR5 expression on CD8+ T cells as well as proliferation and the expression of cytotoxic effector molecules on CXCR5+CD8+ T cells. Our current hypothesis is that IFN-γ+CD4+ T cells are critically important for the development of CXCR5+CD8+ TAb-supp cells, and ongoing studies will continue to investigate the influence these factors have on the novel cell subset.
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Keywords
Immunology, Transplant, Antibody-mediated rejection, IFN-y, CD8+ T cell, CD4+ T cell