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-kappaB 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.
Gelman
Andrew E
AE
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhang
Jidong
J
Choi
Yongwon
Y
Turka
Laurence A
LA
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D000081242:B-Cell Lymphoma 3 Protein; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology*; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D051020:bcl-X Protein
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000943:Antigens, Differentiation; D000081242:B-Cell Lymphoma 3 Protein; C494812:Bcl2l1 protein, mouse; C000631345:Bcl3 protein, mouse; C408982:CPG-oligonucleotide; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases; D011070:Poly I-C