Abstract
PD-1, TIM-3, and LAG-3 are molecules shown to have immune modulatory properties, and although initially classified as indicators of T cell hyporesponsiveness, it has become clear that they are also associated with the normal course of T cell activation. Functional studies have focused mainly on CD8+ T cells during chronic inflammation due to interest in co-opting the cellular immune response to eliminate viral or cancerous threats; however, there remains a relative lack of data regarding the expression of these molecules on CD4+ T cells. Here, we report that expression of the immune checkpoint (IC) molecules PD-1, LAG-3, and TIM-3 are differentially expressed on CD4+ and CD8+ T cells in the allogeneic response resulting from a mixed lymphocyte reaction. In these studies, PD-1 expression is higher on CD4+ T cells compared to CD8+ T cells. In contrast, TIM-3 is expressed at higher levels on CD8+ T cells compared to CD4+ T cells with an apparent reciprocity in that PD-1+ CD4+ T cells are frequently TIM-3lo/−, while TIM-3-expressing CD8+ T cells are largely PD-1lo/−. In addition, there is a decrease in the frequency of TIM-3+ CD4+ cells producing IFN-γ and IL-5 compared to TIM-3+ CD8+ cells. Lastly, the memory T cell phenotype within each IC-expressing subset differs between CD4+ and CD8+ T cells. These findings highlight key differences in IC expression patterns between CD4+ and CD8+ T cells and may allow for more effective therapeutic targeting of these molecules in the future.
Highlights
T cells exposed to chronic antigen stimulation, in the context of viral infection or the tumor microenvironment, are characterized as exhausted upon loss of proliferative potential, cytokine production, and cytotoxicity [1]
Longitudinal analyses of supernatants collected from these cultures showed levels of TNF-α, IL-5, and IL-13 increased over time with steady levels of IFN-γ up to day 7 of mixed lymphocyte reaction (MLR), while T cells alone did not produce detectable levels of cytokine (Figure 1A), as was the case for dendritic cells (DCs) cultured alone
ELISPOT analysis showed cells actively producing IFN-γ when cultured with allogeneic DC, whereas T cells alone exhibited little to no spots (Figure 1B)
Summary
T cells exposed to chronic antigen stimulation, in the context of viral infection or the tumor microenvironment, are characterized as exhausted upon loss of proliferative potential, cytokine production, and cytotoxicity [1]. Accompanied by progressive loss of function, these cells acquire an altered phenotype with accumulated expression of what have been classified as immune checkpoint (IC) molecules, such as PD-1, TIM-3, and LAG-3. Ligand binding to PD-1 and TIM-3 has been shown to exacerbate T cell dysfunction. Several studies have shown that blocking IC interactions restored and/or enhanced T cell effector function [5,6,7]
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