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

Abstract

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-xL 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.

Direct recognition of LPS by human but not murine CD8+ T cells via TLR4 complex

“…The present studies suggest that TLR4 signals directly drive Tc1 development in the presence of TCR or IL-12 signals. While the mechanism is still unclear and currently under investigation, this is in agreement with the previous findings that BLP preferentially promotes human and murine Th1 but not Th2 cell differentiation [7,8] and that TLR agonists selectively stimulate IFN-g but not IL-4 production by human gd T cells [9,10,12]. Our results therefore support current evidence and suggest the existence of a novel type I T-cell development pathway by directly recognising PAMP via TLRs on T cells.…”

“…This was subsequently confirmed in mice [8]. Furthermore, human and murine memory T cells constitutively express surface TLRs and directly recognise TLR agonists [7,9,10]. Moreover, TLR agonists directly promote further TLR expression, survival and the function of NKT and gd T cells [11,12].…”

“…Growing evidence suggests that T cells participate in immune microbial surveillance [7][8][9][10]. We reported for the first time that human CD4 1 T cells express functional TLR2 and that TLR2 signals directly promote T-cell function [7].…”

“…3c). Given the general effect on all types of T cells, the signal via TLR perhaps represents a previously unrecognised (fourth) signal for T-cell activation, differentiation, survival and memory [7][8][9][10][11][12]. Eur.…”

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

“…First, it is unresolved whether TLR agonists always act via APC, or whether they can act directly on the activated T cells themselves. Gelman et al [37] showed that some TLR are expressed by activated T cells, and that addition of the appropriate agonists can enhance T cell survival in a culture model of clonal contraction. For example, agonists of TLR3 and TLR9 promoted survival of previously activated T cells, while agonists of TLR2 and TLR4 did not.…”