CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans

Abstract

T cells are both producers and consumers of cytokines, and autocrine cytokine signaling plays a critical role in T cell immunity. IL-15 is a homeostatic cytokine for T cells that also controls inflammatory immune responses. An autocrine role of T cell-derived IL-15, however, remains unclear. Here we examined IL-15 expression and signaling upon effector T cell differentiation in mice, and, surprisingly, found that CD4 T cells did not express IL-15. CD4 T cells lacked Il15 gene reporter activity, did not contain IL-15 transcripts, and did not produce IL-15Rα, the proprietary IL-15 receptor required for IL-15 trans-presentation. Moreover, IL-15 failed to inhibit Th17 cell differentiation and failed to generate Foxp3+ Treg cells in vitro. IL-2, which utilizes the same IL-2Rβ/γc receptor complex, however, successfully did so. Exogenous IL-15 only exerted bioactivity to control T cell differentiation when trans-presented by IL-15Rα. Consequently, IL-15Rα-bound IL-15, but not free IL-15, suppressed Th17 cell differentiation and induced Treg cell generation. Collectively, these results reveal the absence of an IL-15 autocrine loop in CD4 T cells and strongly suggest that IL-15 trans-presentation by non-CD4 T cells is the primary mechanism via which IL-15 controls CD4 effector T cell differentiation.

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

“…In ASYM plaques, we identified IL-15-IL15RA on CD4 + T cells, an interaction involved in cell proliferation, cell migration, and inhibition of apoptosis 126 . On the other hand, in SYM plaques IL-15-IL2RB on both CD4 + and CD8 + T cells could regulate Th1 reprogramming 127 and differentiation 128 , two functional phenotypes that emerged in SYM plaques by from our CyTOF and scRNA-seq analyses.…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…97 Therefore, rapamycin at moderate concentrations inhibits CD4 + Teff growth but promotes CD4 + Treg growth and function. 111,112 In contrast, IL-15 is necessary for optimal CD8 + Tregs expansion in vivo 113,114 and in vitro. 111,112 In contrast, IL-15 is necessary for optimal CD8 + Tregs expansion in vivo 113,114 and in vitro.…”

“…97 in vitro while they do in vivo. 111,112 In contrast, IL-15 is necessary for optimal CD8 + Tregs expansion in vivo 113,114 and in vitro. 3,54,61 In vitro expansion of CD8 + Tregs in the same conditions used to expand CD4 + Tregs has shown lower suppression activity in some cases but this may be related to the use of culture conditions that are optimal for CD4 + and not CD8 + Tregs.…”

“…Similar increase in CD8 + and CD4 + Tregs (11 to 14-fold) was observed when using an IL-2 mutein molecule 105. Although IL-15 favors thymic development of CD4 + Tregs along with IL-2 through the IL-2Rβ/γc cytokine receptor complex,110 IL-15Ra is not expressed by CD4 + Tregs and these cells respond to IL-15 only when soluble IL-15Ra binds IL-15 and presents it in trans 111. In a model of GVHD in mice, administration of IL-2 antibody complexes and rapamycin was synergic to CD8 + FOXP3 + Tregs increase up to 30-fold whereas CD4 + FOXP3 + Tregs increased 4-fold 32.…”

RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-x L in developing thymocytes

“…Naïve CD4 + T cells were electronically sorted by gating on CD62L + CD44 lo CD25 − cells. Sorted cells were stimulated with platebound antibodies against CD3 and CD28 (each at 1 g/ml) for 5 days, as previously described (61). Cells were cultured for 5 days under nonskewing T H 0 conditions (medium alone) or were differentiated into T H 17 cells with human TGF1 (5 ng/ml; PeproTech), mouse IL-6 (30 ng/ml; BD Biosciences), antibody against mouse IL-4 (10 g/ml; BD Biosciences), and antibody against mouse IFN- (10 g/ml; BD Biosciences).…”