Function and signal transduction

In complete agreement with the expression pattern of IL-7Ra, blocking of IL-7 or lL-7Ra functions results in defective production of lymphocytes but the animals otherwise remain normal. In IL-7 or IL-7Ra null mutant mice, B cell genesis is blocked at the pro-B and pre-B stage, though some leakage into mature B cells does exist. Interestingly, the pro-B cell stage is reduced more in IL-7Ra(-) than IL-7(-) mice, suggesting the presence of another molecule that can substitute IL-7 at the pro-B stage. Identification of this molecule in a thymic stromal cell clone was recently reported. Likewise, thymic cellularity is markedly reduced in IL-7 or IL-7Ra null mutant mice. In the thymus of IL-7Ra null mice, CD44+CD25" double negative cells increase, while later stages including CD44+CD25+ double negative cells are reduced, suggesting a requirement for IL-7 signaling during the shift from double negative to double positive T cell populations. In contrast, the

Figure 1 IL-7Ra expression during lymphocyte differentiation in mouse. HSA and CD25 expression of each stage of B and T cell differentiation is indicated. DN, DP and SP represent double negative, double positive and single positive in terms of CD4 and CD8 expression.

proportion of each T cell subset remains relatively unaffected in the IL-7 null mouse, though thymic cellularity is only 5% of normal. This discrepancy in the phenotype of IL-7 and IL-7Ra null mutant mice again suggests the presence of another molecule bound to IL-7Ra, which is now known as TSLP (thymic stromal-derived lymphopoietin). The only lymphoid cell lineage that is not affected in these mice is natural killer (NK) cells.

Although IL-7 can induce the proliferation of human T and B cells in vitro, its in vivo role in humans is not clear. Two distinct severe combined immunodeficiency (SCID) mutations that have relevance to IL-7 signaling have been reported; one is a mutation in the -yc gene and the other a mutation in the JAK3 gene. As mentioned previously, an association of IL-7Rot with -yc is essential for the IL-7 signal. Moreover, as summarized in Figure 2, signal transduction by the IL-7Ra/-yc complex requires JAK3 tyrosine kinase. Hence, it is conceivable that a null mutation in either of these genes resulted in defective lymphocyte production. Indeed, mice bearing null mutations of either JAK3 or yc genes have severe defects in lymphocyte production. NK cells are also deficient in the yc null mouse. As yc is also involved in the IL-2, IL-4, IL-9, IL-13, and IL-15

receptors, the difference between the ll.-^Rot and yc null mice indicates the involvement of one or more of these signals in NK cell production. However, in human, complete loss of JAK3 or yc causes a phenotype in which T but not B cell lineages are absent. This indirect evidence indicates that the role of II.-"7 signaling in human B lymphopoiesis is redundant.

What is the role of the IL-7 signal in lymphocyte differentiation? Studies on normal pro-B cells indicate that it controls cell cycle progression, particularly entry and maintenance of the S phase. Moreover, evidence suggests that it is involved in stage-specific gene expression such as the VI)J recombinase machinery. As multiple molecules are activated upon stimulation by IL-7, it is conceivable that the II.-7 signal may have multiple functions. Molecules directly associated with the IL-7Ra/-yc complex include JAK1, JAK3 and fyn. The phenotype of the JAK3 null mutant mouse strongly suggests that the JAK3 pathway is essential for the induction of cell proliferation. In fact, the activation of JAK3 upon IL-7 stimulation subsequently activates STAT I. STAT5 and phosphatidylinositol 3-kinase (PI3K) through tyrosine phosphorylation. Evidence indicates that PI3K is essential for cell proliferation. However, if and how STAT1 and 5 are involved in

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