B Cell Depletion Curtails CD4+ T Cell Memory and Reduces Protection against Disseminating Virus Infection

Abstract

Dynamic interactions between CD4+ T cells and B cells are needed for humoral immunity and CD4+ T cell memory. It is not known whether B cells are needed early on to induce the formation of memory precursor cells or are needed later to sustain memory cells. Herein, primary and memory CD4+ T cells responses were followed in wildtype mice that were depleted of mature B cells by anti-CD20 before or different times after acute lymphocytic choriomeningitis virus (LCMV) infection. The antibody treatment led to a 1000-fold reduction in B cell number that lasted 6 weeks. Primary virus-specific CD4+ Th1 cells were generated in B cell-depleted mice, however, there was a decrease in the CD4+Ly6CloTbet+ memory precursor population and a corresponding 4-fold reduction in CD4+ memory cell number. Memory T cells showed impaired cytokine production when they formed without B cells. B cell-depletion had no effect on established memory populations. During disseminating virus infection, B cell depletion led to sustained weight loss, functional exhaustion of CD4+ and CD8+ T cells, and prevented mice from resolving the infection. Thus, B cells contribute to the establishment and survival of memory CD4+ T cells following acute infection and play an essential role in immune protection against disseminating virus infection.

Deficiency of Antigen-Specific B Cells Results in Decreased Trypanosoma cruzi Systemic but Not Mucosal Immunity Due to CD8 T Cell Exhaustion

“…Decreased survival in B cell knockout μMT -/- mice after T. cruzi systemic challenge has been shown previously (16, 26). In addition, our results are similar to recently published data demonstrating that after disseminating virus infection (LCMV-t1b), μMT knockout and anti-CD20 treated mice could not control viral replication, resulting in weight loss and decreased LCMV-specific CD8 + T cell functionality (33). Overall, these previous results combined with our new data suggest that memory CD8 + T cells primed in mice lacking T. cruzi -specific B cells are sufficient to control low levels of tissue parasitism, but eventually become exhausted after systemic challenge due to prolonged exposure to high levels of antigen.…”

“…We and others have shown that CD4 + T cell help is required for effective CD8 + T cell memory (10, 42) and can rescue exhausted CD8 + T cells (43). Work recently published showed that CD4 + T cells are dysfunctional in the absence of B cells in the LCMV model (33). These data support the importance of our work, which for the first time demonstrates the principle that B cell responses are important for preventing the exhaustion of T cells directed against a major human pathogen.…”

Acute and Chronic B Cell Depletion Disrupts CD4+ and CD8+ T Cell Homeostasis and Expansion during Acute Viral Infection in Mice

“…6E). Because CD4 + T cells are critical for CD8 + T cell responses to viral infection (54), the observed impact of B cell depletion on CD8 + T cell function may be due to B cell–induced alterations in CD4 + T cell expansion, function, and memory maintenance, as shown in this study and elsewhere (16, 23, 37). The absence of B cells may thereby also indirectly impact CD8 + T cell memory development, as memory CD8 + T cells derive from the responding Ag-specific effector CD8 + T cell pool (21), and there is a reduction in memory CD8 + T cell numbers following LCMV infection in the absence of B cells (30).…”

“…3). In complementary studies, acute B cell depletion in mice with otherwise intact immune systems impairs adaptive and autoreactive CD4 + T cell responses to Ag challenge, whereas CD8 + T cell reactivity is less affected (16, 23). B cell depletion also reduces the conversion of naive CD44 lo CD62L + CD4 + T cells to an activated phenotype in response to Listeria challenge, whereas CD8 + T cell phenotypes are only modestly affected (16).…”

“…Indeed, T cells derived from μMT mice are unable to develop memory responses sufficient to control persistent viral infection (29), and this effect is independent of B cell Ab production (44, 55). B cells are also required for optimal CD4 + T cell memory generation and recall responses upon secondary infection, a process dependent on B cell MHC class II expression (23, 37). Total and Ag-specific effector, prememory, and T follicular helper CD4 + T cell development was also significantly inhibited in the current study.…”