Assessment of the quality and the breadth of antigen (Ag)-specific T cells in human samples is of paramount importance to elucidate the pathogenesis and to develop new treatments in various diseases. TCR signal strength, mainly controlled by TCR affinity, affects many fundamental aspects of T cell biology, however no current assays for detection of Ag-specific T cells can assess their TCR signal strength in human samples. Here we demonstrated and validated that interferon regulatory factor 4 (IRF4), a transcription factor rapidly upregulated in correlation with TCR signal strength, permits the assessment of the TCR signal strength of Ag-specific cells in human PBMCs and lung tissues. In two separate studies, we identified significant phenotypic and functional differences between high-affinity and low-affinity Ag-specific T cells using the IRF4 assay.
In the first study, we set out to investigate impaired cytolytic functions seen in HIV-specific CD8 T cells in chronic HIV using the IRF4-CD137 assay and demonstrated that HIV-specific CD8 T cells are consistently IRF4lo, reflecting suboptimal TCR signal strength. These low-affinity HIV-specific CD8 T cells are preferentially retained after early infection and remained as a pool of dysfunctional HIV-specific CD8 T cells with low apoptosis profile and a memory phenotype.
In the second study, we aimed to identify differences in flu-specific CD4 T cell response at early and late timepoints post vaccination. We provide evidence that vaccination induced flu-specific T cells was detected using the IRF4 assay. We highlight that using this approach, we were able to visualize the distribution of T cell subsets within flu-specific population. We identified significant phenotypic and functional differences in various T cell subsets within flu-specific populations. Importantly, we found that flu-specific circulating T follicular helper cells (cTfh) expressed the highest levels of IRF4 together with other activation induced markers, suggesting that they are composed of cells with high TCR affinity. We also observed higher expression of CXCR3 in flu-specific cTfh and higher expression of CCR6 in flu-specific T helper cells. This contrast in chemokine receptor expression suggests distinct migratory patterns and destinations between flu-specific CD4 T cell subsets and could result in divergent cell fate.
|Commitee:||Berin, Cecilia, Moran, Thomas M, Gulko, Percio, Lim, Jean|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 82/4(E), Dissertation Abstracts International|
|Subjects:||Immunology, Microbiology, Cellular biology|
|Keywords:||Antigen-specific T cells, IRF4, T cells|
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