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IL-7 is required for survival of most T cell subsets and generally promotes T cell immune responses. Loss of functions of IL-7R in human has been known to cause severe combined immunodeficiency. Somatic gain of function mutations of IL-7R have been found in childhood T-cell acute lymphoblastic leukemia (T-ALL), these mutations usually occur in region of residue 244 in the exon 6 and lead to insertion of multiple amino acids. More recently, polymorphisms in IL-7R have been shown be a risk factor for multiple sclerosis (MS) and some autoimmune diseases. The polymorphysims that affects risk to most of these immunopathologies is T244/I, the same region harboring gain-of-function mutations in T-ALL. To investigate the mechanism of IL-7R variants association with MS and seek new therapeutic approaches directed to IL-7R pathway, we hypothesize that the functional significance of the T244/I polymorphism in IL-7R is related to increased signaling. To test our hypothesis, the T244 and I244 alleles of IL7R are transfected into BaF3 cells. The high risk allele T244 induces stronger Stat5 activation and promotes better survival of BaF3 cells. We further examine the strength of signaling in vivo in mice. IL-7R deficient bone marrow hematopoietic progenitors are transduced by retroviral infection with T244 or I244 allele and transferred to Rag1 deficient mice. Human IL-7R rescues T cell development in mice. Consistent with the in vitro study, the CD8 cells harboring the high risk allele T244 display stronger Stat5 activation compared with cells with I244. Our preliminary study suggests that high risk allele T244 of IL-7R signals stronger than allele I244, and this may promote activation of autoimmune T calls in MS and other autoimmune diseases.

The identification of signals critical for the pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) should contribute to the development of novel, more effective therapeutic strategies. Common gamma-chain signaling cytokines (gammac-cytokines) - interleukins 2, 4, 7, 9 and 15 - differentially regulate T-cell development, survival, proliferation and differentiation. Although studies exist on some individual cytokines, no comprehensive analysis of the effects of the Zc-cytokine family on malignant T cells has been reported. Here, we examined the effect of Zc-cytokines on T-ALL proliferation.Primary leukemic cells were collected at diagnosis from the blood or bone marrow of children with T-ALL. The cells were immunophenotyped and classified according to maturation stage. Proliferative responses to gammac-cytokines were assessed by 3H-thymidine incorporation.All gammac-cytokines promoted proliferation of primary T-ALL cells. Interleukin (IL)-7 was the cytokine that most frequently induced leukemic cell proliferation and promoted the most robust responses. IL-4 preferentially stimulated proliferation of samples with a more mature immunophenotype, whereas CD1a-positive cortical T-ALL cells were less responsive to IL-9. Finally, combinations of two Zc-cytokines showed synergistic or additive proliferative effects.This study indicates that all the gammac-cytokines tested can stimulate proliferation of leukemic T cells and suggests that synergistic effects may occur in vivo. We present the first demonstration that IL-9 and IL-15 can provide a proliferative signal to T-ALL cells. Importantly, our results support the hypothesis that IL-7 may function as a critical regulator of T-ALL and that its activity may be potentiated by other Zc-cytokines.