The lipopolysaccharide adjuvant effect on T cells relies on nonoverlapping contributions from the MyD88 pathway and CD11c+ cells.
Bacterial LPS is a natural adjuvant that induces profound effects on T cell clonal expansion, effector differentiation, and long-term T cell survival. In this study, we delineate the in vivo mechanism of LPS action by pinpointing a role for MyD88 and CD11c(+) cells. LPS induced long-term survival of superantigen-stimulated CD4 and CD8 T cells in a MyD88-dependent manner. By tracing peptide-stimulated CD4 T cells after adoptive transfer, we showed that for LPS to mediate T cell survival, the recipient mice were required to express MyD88. Even when peptide-specific CD4 T cell clonal expansion was dramatically boosted by enforced OX40 costimulation, OX40 only synergized with LPS to induce survival when the recipient mice expressed MyD88. Nevertheless, these activated, but moribund, T cells in the MyD88(-/-) mice acquired effector properties, such as the ability to synthesize IFN-gamma, demonstrating that effector differentiation is not automatically coupled to a survival program. We confirmed this notion in reverse fashion by showing that effector differentiation was not required for the induction of T cell survival. Hence, depletion of CD11c(+) cells did not affect LPS-driven specific T cell survival, but CD11c(+) cells were paramount for optimal effector T cell differentiation as measured by IFN-gamma potential. Thus, LPS adjuvanticity is based on MyD88 promoting T cell survival, while CD11c(+) cells support effector T cell differentiation.
McAleer
Jeremy P
JP
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Zammit
David J
DJ
Lefrançois
Leo
L
Rossi
Robert J
RJ
Vella
Anthony T
AT
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D039521:CD11c Antigen / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D053262:Receptors, OX40 / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D039521:CD11c Antigen; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D053262:Receptors, OX40; D018089:Superantigens; C505717:Tnfrsf4 protein, mouse; D007371:Interferon-gamma