AGE-DEPENDENT INTESTINAL LYMPHOPROLIFERATIVE DISORDER DUE TO STEM-CELL FACTOR-RECEPTOR DEFICIENCY - PARAMETERS IN SMALL AND LARGE-INTESTINE

Signaling through c-Kit/stem cell factor (SCF) is crucial for normal d evelopment of erythroid and myeloid hematopoietic precursors and of me lanocytes and germ cells, While peripheral lymphoid populations of W/W -v and Sl/Sl(d) mice appear normal, we demonstrated that the intraepit helial lymphocyte (IEL) populations of small (SI) and large (LI) intes tine were significantly affected. IEL populations of young W/W-v anima ls were indistinguishable from those of their control littermates, but an age-dependent decrease in SI and LI TCR gamma delta IEL occurred i n c-Kit mutant mice. In SI, but not in LI, this diminution was accompa nied by gross expansion of TCR alpha beta IEL that resulted in signifi cantly increased IEL:epithelial cell ratios in c-Kit mutant mice, Brom odeoxyuridine labeling studies revealed that the increase in cell numb ers was due to lymphoproliferation that occurred in situ, Interestingl y, TCR gamma delta IEL expressed cell surface c-Kit, while the expandi ng population of TCR alpha beta IEL did not. Analysis of radiation bon e marrow chimeras demonstrated that the dysregulation required either disruption of stromal cell SCF or IEL c-Kit and showed that the effect on IEL or their precursors was not due to other changes in the intest inal microenvironment, Lamina propria T cell populations in these mice were unaffected, reinforcing the idea that the developmental requirem ents of these gut-resident lymphocyte populations are distinct, Overal l, the results demonstrated that the development of intestinal TCR gam ma delta IEL, regardless of location, shares common requirements for S CF, while SI and LI TCR alpha beta IEL may develop along distinct path ways, Possible mechanisms for the loss of proliferative regulation in gut T cells in c-Kit/SCF deficiency are discussed.