RESEARCH ARTICLE B Cells and Programmed Death-Ligand 2 Signaling Are Required for Maximal Interferon-γ Recall Response by Splenic CD4+

CD4+ T cells producing interferon-γ are crucial for protection againstMycobacterium tuber-culosis infection and are the cornerstone of tuberculosis vaccination and immunological diagnostic assays. Since emerging evidence indicates that B cells can modulate T cell responses toM. tuberculosis infection, we investigated the contribution of B cells in regulat-ing interferon-γ recall response by memory Thelper1 cells specific for Ag85B, a leading can-didate for tuberculosis sub-unit vaccines. We found that B cells were able to maximize the reactivation of CD4+ memory T cells and the interferon-γ response against ex vivo antigen recall in spleens of mice vaccinated with Ag85B. B cell-mediated increase of interferon-γ response was particular evident for high interferon-γ producer CD4+ memory T cells, likely because those T cells were required for triggering and amplification of B cell activation. A positive-feedback loop of mutual activation between B cells, not necessarily antigen-experienced but with integral phosphatidylinositol-3 kinase (PI3K) pathway and a peculiar interferon-γ-producing CD4highT cell subset was established. Programed death-ligand 2 (PD-L2), expressed both on B and the highly activated CD4high T cells, contributed t