The roles of T lymphocytes in the central nervous system (CNS) are diverse; their roles in the injured CNS have been reported to be both detrimental and advantageous. Hence, an investigation of the effects of specific subsets of T cells on neurons may provide an insight into the interaction between the nervous system and the immune system. In the present study, we demonstrate that a specific subset of T lymphocytes enhanced neurite outgrowth in vitro. When cultured T helper type 1 (Th1) cells were co-cultured with cortical neurons, neurite outgrowth from neurons was enhanced; however, the same was not observed when Th2 or nave T cells were used. We observed that the promotion of neurite outgrowth by Th1 cells was completely inhibited by anti-interferon gamma (IFN-gamma) neutralizing antibody, but that IFN-gamma did not directly promote neurite growth. Furthermore, experiments using knockout mice revealed that semaphorin 4A (Sema4A) but not Sema7A was required for the effect produced by Th1 cells. These results demonstrate that Sema4A and IFN-gamma expressed in Th1 cells play a critical role in enhancing neurite outgrowth from cortical neurons. (C) 2010 Elsevier Inc. All rights reserved.