Pictured from left to right: Norifumi Iijima and Akiko Iwasaki

Pictured from left to right: Norifumi Iijima and Akiko Iwasaki

A Local Macrophage Chemokine Network Sustains Protective Tissue-resident Member CD4 T Cells

Science. 2014 Oct 3;346(6205):93-8. doi: 10.1126/science.1257530. Epub 2014 Aug 28.

Despite large investment and effort, vaccines that rely on T cells have not been successful. Unlike antibody-based vaccines, T cell-based vaccines rely on the cellular recruitment to the site of infection for protection. However, how T cells migrate and provide protective immunity to pathogens, particularly in tissues such as the reproductive tract, remains unknown. In this study, we addressed the importance of local vs. circulating memory CD4 T cells in protection against a lethal mucosal viral challenge with herpes simplex virus 2 (HSV-2).  By using parabiotic mice, we demonstrate a striking superiority of tissue-resident memory CD4 T cells in protection, while circulating memory CD4 T cells fail to suppress viral replication and a half of this group die from HSV-2 infection. We further demonstrate that vagina-resident pool of memory CD4 T cells are maintained by local macrophages that secrete chemokines, within a structure we call “memory lymphocyte clusters” (MLC). MLCs are found just underneath the stratified epithelial layer of the vaginal mucosa, and are distinct from tertiary lymphoid organs in that MLC consists only of memory lymphocytes, is devoid of high endothelial venules, efferent lymphatics and organized T and B cell zones. MLCs are present in humans with genital herpes, and represent a local surveillance post that can deploy memory lymphocytes to rapidly and efficiently prevent mucosal infections with HSV. Therefore, vaccine strategies capable of establishing MLC may confer benefit in promoting protective immunity against pathogens that enter through mucosal tissues. PubMed: 25170048