Expression of activation‐induced cytidine deaminase enhances the clearance of pneumococcal pneumonia: evidence of a subpopulation of protective anti‐pneumococcal B1a cells

Abstract

SummaryWe describe a protective early acquired immune response to pneumococcal pneumonia that is mediated by a subset of B1a cells. Mice deficient in B1 cells (xid), or activation-induced cytidine deaminase (AID À/À ), or invariant natural killer T (iNKT) cells (Ja18 À/À ), or interleukin-13 (IL-13 À/À ) had impaired early clearance of pneumococci in the lung, compared with wild-type mice. In contrast, AID À/À mice adoptively transferred with AID +/+ B1a cells, significantly cleared bacteria from the lungs as early as 3 days post infection. We show that this early bacterial clearance corresponds to an allergic contact sensitivity-like cutaneous response, probably due to a subpopulation of initiating B1a cells. In the pneumonia model, these B1a cells were found to secrete higher affinity antigen-specific IgM. In addition, as in contact sensitivity, iNKT cells were required for the anti-pneumococcal B1a cell initiating response, probably through early production of IL-13, given that IL-13 À/À mice also failed to clear infection. Our study is the first to demonstrate the importance of AID in generating an appropriate B1a cell response to pathogenic bacteria. Given the antibody affinity and pneumonia resistance data, natural IgM produced by conventional B1a cells are not responsible for pneumonia clearance compared with the AID-dependent subset.

Functions of Exosomes and Microbial Extracellular Vesicles in Allergy and Contact and Delayed-Type Hypersensitivity

“…Such mini-APC exosomes with surface CD1d may stimulate tissue iNKT cells to release allergy-promoting Th2 cytokines, like IL-4 and IL-13, after interaction with host, plant or mite glycolipids. As a result, these CD1d-dependent iNKT cells may induce allergic responses against glycolipid Ag with the release of IL-4, as we showed previously in contact hypersensitivity [107], or IL-13 reacting against polysaccharides from bacteria, as we showed in a murine model of pneumococcal pneumonia [108]; or the plant pollens [101], as a requirement for eventual effector Th1 cell participation.…”

“…These B1a cells are activated by hapten-self complexes induced by application of the relevant hapten on mouse skin, which completes the tolerogenic procedure [2]. The strict Ag-specificity of the participating B1a cell subpopulation is due to activation induced deaminase (AID), a nuclear mutating enzyme, that acted on the DNA of these cells prior to immunization to cause mutations in the immunoglobulin V-region genes, thus encoding the Ag-specific combining sites of Ab heavy and light chains [108,194,195]. …”

“…Characteristically, the special B1a cells, having only a few immunoglobulin V-region mutations mediated by AID that account for their strict Ag-specificity, are able to respond within minutes of hapten-self primary skin immunization, documented to occur in separate systems by just 18 minutes [107], 30 minutes [108] or one hour [197] after the original skin sensitization. As a consequence, the exosome sensitizing Ab light chains with few mutations are of low affinity for Ag, compared to their associated isolated heavy chains or the parental whole Ab.…”

“…Regarding the suppressor exosomes, Ag-specific Ab free light chains [2] are produced by previously activated B1a cells and have low numbers of AID-mediated V-region mutations [108,195], and bind to the surface of CD8 pos Ts cell-derived exosomes in a manner that keeps their combining sites available and allows quite Ag-specific function [2]. Note that tests in Fc receptor deficient mice showed that these receptors are not involved in Ab light chain binding [201], as expected since they have no Fc portion.…”

Vaccination with a live attenuated Acinetobacter baumannii deficient in thioredoxin provides protection against systemic Acinetobacter infection

“…Furthermore, Yamamoto et.al. [37], demonstrated that a subset of peritoneal cavity originating B1a cells, which secreted higher affinity antigen-specific IgM, was essential for mediating early protection against pneumococci. These prior studies suggest a possible mechanism for protection against otherwise lethal WT A. baumannii via vaccination with the Δ trxA mutant in our studies.…”