Early Lymphocyte Expansion Is Severely Impaired in Interleukin 7 Receptor-deficient Mice By Jacques J. Peschon, Philip J. Morrissey, Kenneth H. Grabstein,

Summary Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7. T he development of lymphoid cells from muhipotential progenitors is dependent upon growth, survival, and differentiation factors produced by various stromal cells. Long- term cultures supporting the growth of murine B lineage cells from uncommitted precursors can be established from adult bone marrow and have been instrumental in defining factors that influence B cell development (1, 2). IL-7 was identified and cloned based upon its ability to induce short- term proliferation of B cell progenitors in the absence of stromal cells (3). The requirement for IL-7 in the prolifera- tion of B cell precursors has been clearly established in that stromal cell variants that no longer express IL-7 are incapable of efficiently supporting B ceU progenitor growth, and neu- tralizing antibodies to IL-7 or IL-7R severely inhibit B cell development in vitro and in vivo (4-6). Evidence suggests that the IL-7-responsive B lineage popu- lation displays an early/late pro-B cell phenotype character- ized by the expression of B220, heat stable antigen (HSA), and leukosialin (CD43), the presence of D-J and V-D-J rear- rangements and the absence of surface IgM (7). Less mature B lineage cells do not proliferate or differentiate in response to IL-7 in vitro, although they do express IL-7R (8). IL-7R expression is lost after productive light chain rearrangement in pre-B ceils, and thus subsequent stages of B cell matura- tion are likely to be directly IL-7 independent (9). The role of IL-7 in T cell development is less well defined. IL-7 is expressed in the thymus and has been shown to stimu- late the growth of immature CD4-/CD8- adult and fetal thymocytes (10, 11) and promote rearrangement of T cell receptor 3 and 3, chains in fetal thymus and fetal liver culture systems (12, 13). Additionally, treatment of mice with neu- tralizing antibodies to IL-7 or IL-7R results in thymic hypoplasia (5, 6), and overexpression of IL-7 in transgenic mice perturbs thymocyte cellularity (14). However, it is not known to what extent T cell development within the thymus is IL-7 dependent and which of the thymic subpopulations have specific requirements for IL-7-induced proliferation and survival in vivo. We have taken a genetic approach to further elucidate the role of IL-7 and its high affinity receptor in the proliferation and maturation of B and T lineage cells in vivo by analyzing lymphoid development in mice lacking the high affinity IL- 7R. Results obtained from these analyses implicate IL-7R as a critical signaling molecule in the proliferation of early B cell progenitors undergoing heavy chain rearrangements and in early thymocyte expansion prior to the acquisition of rearranged T cell receptor genes.