title: B Cells and Programmed Death-Ligand 2 Signaling Are Required for Maximal Interferon-γ Recall Response by Splenic CD4⁺ Memory T Cells of Mice Vaccinated with Mycobacterium tuberculosis Ag85B.
abstract: CD4+ T cells producing interferon-γ are crucial for protection against Mycobacterium tuberculosis infection and are the cornerstone of tuberculosis vaccination and immunological diagnostic assays. Since emerging evidence indicates that B cells can modulate T cell responses to M. tuberculosis infection, we investigated the contribution of B cells in regulating interferon-γ recall response by memory Thelper1 cells specific for Ag85B, a leading candidate 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 to the increase of interferon-γ recall response through a PD1-independent pathway. In B cell-deficient mice, interferon-γ production and activation of Ag85B-specific CD4+ T cells were blunted against ex vivo antigen recall but these responses could be restored by adding B cells. On the other hand, B cells appeared to down-regulate interleukin-22 recall response. Our data point out that nature of antigen presenting cells determines quality and size of T cell cytokine recall responses. Thus, antigen presenting cells, including B cells, deserve to be considered for a better prediction of cytokine responses by peripheral memory T cells specific for M. tuberculosis antigens. We also invite to consider B cells, PD-L2 and PI3K as potential targets for therapeutic modulation of T cell cytokine responses for tuberculosis control.
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Riccomi
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Palma
mesh_terms: D000217:Acyltransferases / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005260:Female; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D000217:Acyltransferases; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D007371:Interferon-gamma; D007378:Interleukins; D058539:Phosphatidylinositol 3-Kinase; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D000097043:Interleukin-22; C556978:Pdcd1lg2 protein, mouse; C121433:antigen 85B, Mycobacterium tuberculosis