T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with Disseminated Chlamydia muridarum Genital Tract Infection

Abstract

CD4 T cells and antibody are required for optimal acquired immunity to genital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice with CM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal for and mice, in which IFN-γ signaling was absent, and for mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM to mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescued mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

Innate IFN-γ Is Essential for Systemic Chlamydia muridarum Control in Mice, While CD4 T Cell-Dependent IFN-γ Production Is Highly Redundant in the Female Reproductive Tract

“…Recently, Poston et al have shown that T cell-independent IFN cooperates with B cells to prevent lethal dissemination caused by a highly virulent C. muridarum strain CM001 (17). Our data add to previous findings by showing ex vivo IFN secretion on the surface of CD11b+ NK1.1+ cells, indicating that group 1 ILCs elicit protective function, as least in part, by their production of IFN in the absence of T cells.…”

“…In contrast, nude mice and mice lacking MHC class II-restricted CD4 T cells shed persistent high levels of bacteria from the FRT without showing obvious signs of wasting (15)(16)(17). While a large body of evidence points to a role for Th1, but not other Th lineage cells in protective immunity against Chlamydia (14,(18)(19)(20)(21)(22)(23).…”

Encapsulation of Recombinant MOMP in Extended-Releasing PLGA 85:15 Nanoparticles Confer Protective Immunity Against a Chlamydia muridarum Genital Challenge and Re-Challenge

“…The heightened protective chlamydial-specific Th1 cytokines (IFN-g and IL-2) and CD4 + memory and effector T-cells produced after immunization of mice (SC and IN) corroborate reports of Th1 immune effectors that can clear a C. muridarum vaginal challenge (10,40). Indeed, the protective role of Th1 cytokines has directly been correlated with IFN-g-mediated Chlamydia killing by activating T-cells (43,44). In line with our observation, CD4 + T-cells driven-immune responses with pronounced IFN-g production are reportedly adequate for protection against C. muridarum infections in the genital tract (45)(46)(47).…”

Diversity in the T cell response to Chlamydia-sum are better than one

“…CD4 T cells are likely the main source of IFN-γ in these scenarios since NK or CD8 T cell depletion during primary or secondary Cm infection causes only mildly increased bacterial burdens [24, [29], [48]. This might suggest that CD4 T cell production of IFN- γ to direct antibody class-switching is critical to preventing disseminated primary infection, and this notion is supported by a recent study [47]. The source of this protective IFN-γ is likely to be Tfh cells in the draining lymph node, a CD4 subset that has not been carefully studied in the context of Chlamydia infection.…”

“…In contrast IFN-γ-deficient mice shed low levels of bacteria from the FRT, while B cell-deficient mice clear Cm from the FRT completely [22] [33]. Both mice, however, develop severe concurrent systemic infection, indicating that IFN-γ and humoral responses may be necessary for containing disseminating infection [33, [46, [47]. CD4 T cells are likely the main source of IFN-γ in these scenarios since NK or CD8 T cell depletion during primary or secondary Cm infection causes only mildly increased bacterial burdens [24, [29], [48].…”