Signal regulatory protein alpha (SIRP alpha) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Wild-type (WT) C57BL/6 mice are known to be resistant to Leishmania major infection. We here found that C57BL/6 mice that express a mutant version of SIRPa lacking most of the cytoplasmic region manifested increased susceptibility to L major infection, characterized by the marked infiltration of inflammatory cells in the infected lesions. The numbers of the parasites in footpads, draining lymph nodes and spleens were also markedly increased in the infected SIRP alpha mutant mice, compared with those for the infected WT mice. In addition, soluble leishmanial antigen-induced production of IFN-gamma by splenocytes of the infected SIRP alpha mutant mice was markedly reduced. By contrast, the ability of macrophages of SIRP alpha mutant mice to produce nitric oxide in response to IFN-gamma was almost equivalent to that of macrophages from WT mice. These results suggest that SIRP alpha is indispensable for protective immunity against L major by the induction of Th1 response. (C) 2010 Elsevier Inc. All rights reserved.