K. Laky et al., AGE-DEPENDENT INTESTINAL LYMPHOPROLIFERATIVE DISORDER DUE TO STEM-CELL FACTOR-RECEPTOR DEFICIENCY - PARAMETERS IN SMALL AND LARGE-INTESTINE, The Journal of immunology, 158(3), 1997, pp. 1417-1427
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.