Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis

Abstract

Little is known about how the microbiota regulates T cell proliferation and whether spontaneous T cell proliferation is involved in the pathogenesis of inflammatory bowel disease. In this study, we show that stimulation of innate pathways by microbiota-derived ligands and antigen-specific T cell stimulation are both required for intestinal inflammation. Microbiota-derived ligands promoted spontaneous T cell proliferation by activating dendritic cells (DCs) to produce IL-6 via Myd88, as shown by the spontaneous proliferation of T cells adoptively transferred into specific pathogen–free (SPF) RAG−/− mice, but not in germfree RAG−/− mice. Reconstitution of germfree RAG−/− mice with cecal bacterial lysate–pulsed DCs, but not with IL-6−/− or Myd88−/− DCs, restored spontaneous T cell proliferation. CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant microbiota antigen, induced colitis in SPF RAG−/− mice. Blocking the spontaneous proliferation of CBir1 Tg T cells by co-transferring bulk OT II CD4+ T cells abrogated colitis development. Although transferred OT II T cells underwent spontaneous proliferation in RAG−/− mice, the recipients failed to develop colitis because of the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both spontaneous proliferation of T cells driven by microbiota-derived innate signals and antigen-specific T cell proliferation.

The role of gut microbiota in immune homeostasis and autoimmunity

“…43 An elegant study by Feng et al demonstrated that microbiotaderived innate and TCR specific signals are both required for the induction of disease using a murine model of IBD. 77 Accordingly, it was shown that homeostatic proliferation of transferred T cells were only observed in SPF but not in GF Rag 2/2 mice, indicating that the presence of the gut microbiota is required for the T cell proliferation. This microbiota-mediated T cell proliferation requires a MyD88-dependant IL-6 induction in DCs.…”

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

“…8B, are responsible for the induction of colitis when transferred in the absence of Treg cells. Antigenic peptides derived from the enteric bacteria and presented by MHCII molecules have been shown to be responsible for this TCR-driven fast proliferation whereas the slow proliferation is independent of MHCII molecules and IL-7-driven [26][27][28][29][30]. We took advantage of this model to determine whether upon transfer into Cd3e 5/ 5 x MHCII / mice, MLN-resident inflammatory M s isolated from MHCII-sufficient, colitic mice were capable of rescuing the fast proliferation of cotransferred CD4 + T cells and their differentiation into IFN-γ-producing effectors.…”

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

“…The second type of LIP is thought to be more dependent on TCR-Ag-MHC interactions and leads to the rapid division of T cells and the upregulation of activation markers such as CD44. This fast proliferation is referred to as spontaneous proliferation and is similar to cognate Ag-induced proliferation (6), except that the peptide Ags involved in this signal are thought to be either self-or commensal-derived as the absence of the microbiota in germ-free mice virtually abolished the spontaneous proliferation of transgenic CD4 T cells (7). Additional evidence for the involvement of peptide-loaded MHC is that the complexity of the TCR repertoire influences the extent of proliferation, with only polyclonal T cells being able to inhibit the proliferation of T cells in lymphopenic hosts (8,9).…”

“…The two factors known to be involved in stimulating LIP are cytokines such as IL-7 and TCR-self-Ag MHC interactions (7,27). Whether costimulatory molecules play a role in promoting LIP is not clear because one group showed that CD4 T cell LIP is enhanced by CD28 signals (11), whereas another report showed that CD28, CD40, and 4-1BB signals are not required for LIP (10).…”