Maintaining T cell homeostasis

SH2 domain-containing protein tyrosine phosphatase 1 (SHP1; encoded by PTPN6) negatively regulates immune signalling, and mice with inactivating mutations in Ptpn6 (also known as motheaten mice) suffer from severe inflammation and autoimmune disease. SHP1 is expressed by all haematopoietic cells, so Johnson et al. generated transgenic mice with a T cell-specific deletion of Ptpn6 (Ptpn6^fl/flCd4–Cre mice) to study the T cell-intrinsic roles of SHP1.

Credit: NPG

Studies using motheaten mice had previously indicated that SHP1 negatively regulates T cell receptor (TCR) signalling, thereby affecting T cell development and function. However, T cell development was found to be normal in Ptpn6^fl/flCd4–Cre mice, which — unlike motheaten mice — also lacked any signs of inflammation or autoimmunity.

SHP1 seems to control the IL-4-driven proliferation of memory-phenotype T cells

In the periphery, the percentage of CD44^hi T cells was increased in naive Ptpn6^fl/flCd4–Cre mice compared with control Ptpn6^fl/fl mice (in which SHP1 was not deleted). SHP1-deficient CD44^hi T cells had a memory phenotype and could be classified into central and effector memory T cell subsets. As these memory-like T cells developed even in the absence of a specific endogenous antigen, the authors suggest that SHP1 might suppress the expansion of the naturally occurring memory-phenotype T cell population in the steady state.

TCR sensitivity was found to be normal in peripheral SHP1-deficient CD44^low T cells, as assessed using in vitro proliferation and cytokine production assays, which indicated that SHP1 has a TCR-independent homeostatic role. Notably, in vitro culture of SHP1-deficient T cells for 3 days in the presence of interleukin-2 (IL-2) resulted in increased numbers of IL-4-producing T cells compared with control SHP1-sufficient T cells. The preferential differentiation towards the T helper 2 cell phenotype in the absence of SHP1 was due to defective dephosphorylation of signal transducer and activator of transcription 6 (STAT6) downstream of IL-4 receptor (IL-4R) signalling. This skewing was also reflected by the high levels of IgE in Ptpn6^fl/flCd4–Cre mice.

Finally, analysis of chimeric mice showed that SHP1 deficiency promoted expansion of the CD44^hi T cell population in a cell-intrinsic manner. Moreover, the increase in the number of SHP1-deficient CD44^hi T cells could be rescued by the deletion of IL-4. Thus, SHP1 seems to control the IL-4-driven proliferation of memory-phenotype T cells through the negative regulation of IL-4R signalling. Future studies are needed to clarify whether SHP1 has additional roles in antigen-stimulated T cells.