Requirement of microbiota adjuvanticity for T cell spontaneous proliferation and induction of experimental colitis (47.8)

Abstract

Abstract Homeostatic T cell proliferation has been implicated in various immune-related diseases, including experimental colitis. However, little is known about how microbiota regulate T cell proliferation in lymphopenic hosts, and the role of T cell spontaneous proliferation (SP) in the pathogenesis of colitis. In this report, we show that both microbiota adjuvants and antigens are required for chronic intestinal inflammation. Microbiota ligands provide adjuvant activity to stimulate T cell SP by activating dendritic cells (DC) to produce IL-6 via a Myd88-dependent pathway. This was demonstrated by SP of adoptively transferred T cells in specific pathogen free (SPF) RAG-/- mice but not in germ-free RAG-/- mice. Reconstitution with cecal bacterial lysate-pulsed wild type DC but not with IL-6-/- or Myd88-/- DC restored T cell SP in germ-free RAG-/- mice. Adoptive transfer of CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant commensal bacterial flagellin antigen, induced colitis in SPF RAG-/- mice. Blockade of CBir1 Tg T cell SP by adoptive transfer of bulk OT II CD4+ T cells abrogated colitis development. Although adoptively transferred OT II T cells underwent SP in RAG-/- mice, the recipient mice failed to develop colitis due to the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both microbiota adjuvant-driven T cell SP and microbiota antigen-specific T cell proliferation.