Production of T and B lymphocytes occurs primarily in the thymus and bone marrow during peri-natal life, but the lymphopoietic activity in both of these organs declines with maturity. This proposal hypothesizes that mesenteric and other mesenchyme-derived tissues constitute alternative sites of T and B cell lymphopoiesis throughout life and may become more important with the decline of lymphopoiesis in bone marrow and thymus. The selection of mesenchymal tissues is based upon phylogenetic and ontogenetic evidence of lymphoid progenitor residence and activity in these tissue sites.
The specific aims are as follows: (A) To characterize in detail subpopulations of immature and mature hematopoietic cells resident in human fetal omentum and intestine and in human adult gut-associated tissues (gut epithelium, lamina propria and mesentery), as compared to """"""""conventional"""""""" hematopoietic tissues of fetal and post-natal life. (B) To characterize the potential of lymphoid progenitor cells from these fetal and adult tissues to give rise to mature lymphocyte subsets by in vitro cultures and by SCID mouse engraftments. (C) To characterize T cell V gene usage and functional diversity in these mesenchyme-derived tissues in fetal and post-natal development. (D) To determine the functional specificities of lymphocytes developing from these alternative lymphopoietic tissues with respect to the potential for cytokine production and self-reactivity. These systematic studies will shed light on mechanisms involved in the maintenance of peripheral T and B cell population numbers and repertoires, in the face of declining thymus and bone marrow production, by identifying and characterizing subsets of lymphoid precursors as well as functional T and B cells in alternative tissues. These studies will further provide an understanding of the possible pathophysiological consequences of populating the immune system with lymphoid cells from these alternative sites of lymphopoiesis.
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