T helper cells localized to the intestinal lamina propria (LP) participate in protective immune responses and are involved in the pathogenesis of inflammatory bowel disease (IBD). Thus, the study of LP CD4+ T cells provides a unique opportunity for examination of intrinsic mechanisms involved in the induction and delivery of effector immune responses in a critical mucosal barrier. The mechanisms involved in the immunoregulation responsible for downregulation of T cell responses in this tissue are poorly understood. Thus, a detailed understanding of the immunobiology of CD4+ LP T cells would enhance our ability to regulate mucosal immune responses in both disease prevention and treatment. To address how the intestinal environment influences the activation state and functional differentiation of LP T cells we utilized DO11.10 T cell receptor (TCR) transgenic (Tg) mice specific for a peptide of chicken ovalbumin (OVA). Based on our previous studies we hypothesized that recurrent activation by oral Ag promotes the generation of effector T cells in the LP. In the current proposal we will utilize two novel systems to study Ag-specific mechanisms for generating effector T cells in the LP. First, we will use bone marrow (BM) from D011.10 x RAG-1-/- and BALB/c mice to generate mixed BM chimeras. In these mice a significant population of naive Tg+ T cells are present in the LP which allows us to assess the effects of oral Ag and Ag priming on differentiation of naive LP T cells. In addition, we have adapted an adoptive transfer model for studying Tg T cell responses in normal BALB/c mice. In this system LP Tg T cell populations will be generated from peripheral populations with Ag priming (i.p. OVA/CFA) as might be occur in normal mice after peripheral immune responses. This model will be utilized to study the effects of oral Ag on an already primed population of T cells. Taken together these models will allow us to address fundamental questions regarding the functional differentiation of LP T cells from naive as well as activated precursors. These models will be used in Aim 1 to examine the role of antigen in the generation of effector T cells in the LP. Studies in Aims 2 will address the role of B7-1 and B7-2-mediated T cell costimulation in the functional differentiation of LP T cells. Studies in Aim 3 will use D011.10 x lpr/lpr mice to address the role of CD95- mediated cell death (AICD) in LP T cell functional differentiation. In summary, these studies will utilize the Ag-specific DO11.10 TCR Tg model to address mechanisms involved in the generation and maintenance of effector T cells in the LP.
