Toll-Like Receptor Ligands Directly Promote Activated CD4⁺ T Cell Survival

Toll-like receptor (TLR) engagement by pathogen-associated molecular patterns (PAMPs) is an important mechanism for optimal cellular immune responses. APC TLR engagement indirectly enhances activated CD4⁺ T cell proliferation, differentiation, and survival by promoting the up-regulation of costimulatory molecules and the secretion of proinflammatory cytokines. However, TLRs are also expressed on CD4⁺ T cells, suggesting that PAMPs may also act directly on activated CD4⁺ T cells to mediate functional responses. In this study, we show that activated mouse CD4⁺ T cells express TLR-3 and TLR-9 but not TLR-2 and TLR-4. Treatment of highly purified activated CD4⁺ T cells with the dsRNA synthetic analog poly(I:C) and CpG oligodeoxynucleotides (CpG DNA), respective ligands for TLR-3 and TLR-9, directly enhanced their survival without augmenting proliferation. In contrast, peptidoglycan and LPS, respective ligands for TLR-2 and TLR-4 had no effect. Enhanced survival mediated by either poly(I:C) or CpG DNA required NF-κB activation and was associated with Bcl-x_L up-regulation. However, only CpG DNA, but not poly(I:C)-mediated effects on activated CD4⁺ T cells required the TLR/IL-1R domain containing adaptor molecule myeloid differentiation factor 88. Collectively, our results demonstrate that PAMPs can directly promote activated CD4⁺ T cell survival, suggesting that TLRs on T cells can directly modulate adaptive immune responses.