A Role for Thymic Stromal Lymphopoietin in CD4⁺ T Cell Development

Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γ_c. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γ_c/TSLPR double KO mice had a greater lymphoid defect than γ_c KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γ_c KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γ_c KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4⁺ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4⁺ T cells from TSLPR KO mice expanded less efficiently than WT CD4⁺ T cells in irradiated hosts, and TSLP preferentially expanded CD4⁺ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4⁺ T cells.