S AMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4⁺ T cells expressing the α_Eβ₇ integrin. Although α_Eβ₇⁺CD4⁺ T cells possess a regulatory phenotype (CD25⁺, L-selectin^lo, and CD45RB^lo), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4⁺ T cells, although the CD4⁺CD25⁺ subset, which overlaps with the α_Eβ₇⁺CD4⁺ subset, prevents colitis. The α_Eβ₇⁺CD4⁺ T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA⁺ cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4⁺ T cells increases ileitis severity in SCID mice compared with transfer of CD4⁺ T cells alone. SAMP1/YitFc B cells prevent α_Eβ₇⁺CD4⁺ T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis.