CD4+ αβ T cells from either normal C57BL/6 (B6) or MHC-II-deficient (Aα−/− or Aβ−/−) B6 donor mice engrafted into congenic immunodeficient RAG1−/− B6 hosts induced an aggressive inflammatory bowel disease (IBD). Furthermore, CD4+ T cells from CD1d−/− knockout (KO) B6 donor mice but not those from MHC-I−/−(homozygous transgenic mice deficient for β 2-microglobulin) KO B6 mice induced a colitis in RAG−/− hosts. Abundant numbers of in vivo activated (CD69 high CD44 high CD28 high) NK1+ and NK1− CD4+ T cells were isolated from the inflamed colonic lamina propria (cLP) of transplanted mice with IBD that produced large amounts of TNF-α and IFN-γ but low amounts of IL-4 and IL-10. IBD-associated cLP Th1 CD4+ T cell populations were polyclonal and MHC-II-restricted when derived from normal B6 donor mice, but oligoclonal and apparently MHC-I-restricted when derived from MHC-II-deficient (Aα−/− or Aβ−/−) B6 donor mice. cLP CD4+ T cell populations from homozygous transgenic mice deficient for β 2-microglobulin KO B6 donor mice engrafted into RAG−/− hosts were Th2 and MHC-II restricted. These data indicate that MHC-II-dependent as well as MHC-II-independent CD4+ T cells can induce a severe and lethal IBD in congenic, immunodeficient hosts, but that the former need the latter to express its IBD-inducing potential.