Conditions That Diminish Myeloid-Derived Suppressor Cell Activities Stimulate Cross-Protective Immunity

Abstract

Immunity conferred by conventional vaccines is restricted to a narrow range of closely related strains, highlighting the unmet medical need for the development of vaccines that elicit protection against multiple pathogenic serotypes. Here we show that a Salmonella bivalent vaccine comprised of strains that lack and overproduce DNA adenine methylase (Dam) conferred cross-protective immunity to salmonella clinical isolates of human and animal origin. Protective immunity directly correlated with increased levels of cross-reactive opsonizing antibodies and memory T cells and a diminished expansion of myeloid-derived suppressor cells (MDSCs) that are responsible for the immune suppression linked to several conditions of host stress, including chronic microbial infections, traumatic insults, and many forms of cancer. Further, aged mice contained increased numbers of MDSCs and were more susceptible to Salmonella infection than young mice, suggesting a role for these cells in the immune declines associated with the natural aging process. These data suggest that interventions capable of reducing MDSC presence and activities may allow corresponding increases in B-and T-cell stimulation and benefit the ability of immunologically diverse populations to be effectively vaccinated as well as reducing the risk of susceptible individuals to infectious disease.

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…Previously, the expansion of myeloidderived suppressor cells (i.e. MDSCs) was reported in mice infected with both an aroA mutant and WT Salmonella and these MDSCs inhibited antigen-specific CD4 1 T-cell proliferation [39]. Likewise, CD11b 1 Gr-1 1 inflammatory myeloid cells obtained from RASV-infected MyD88 À/À mice showed suppression against OT-II CD4 1 cell proliferation when there were equivalent numbers of myeloid cells and CD4 1 T cells (Supporting Information Fig.…”

CD11b+Ly6ChiLy6G−Immature Myeloid Cells Recruited in Response to Salmonella enterica Serovar Typhimurium Infection Exhibit Protective and Immunosuppressive Properties

“…Furthermore, early studies linked NO-producing macrophage precursors to S. Typhimurium-induced immunosuppression and protective immunity against S. Typhimurium to diminished expansion of CD11b ϩ Gr-1 ϩ cells (16,17). Several recent studies have associated CD11b…”

“…Although immature myeloid cells play a critical role in the protective host response to infection (14), several early studies have linked nitric oxide (NO)-producing macrophage precursors to immunosuppression in salmonellosis (16). Murine immature myeloid cells express surface CD11b and Gr-1 (13) and have been found in spleens of mice infected with S. Typhimurium (17,18).…”

Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease

“…These findings suggest that MDSCs play a role in TB pathogenesis and the increased numbers of these cells in old age may contribute to the reduced immunity to TB in some older adults. Similarly, Heithoff et al (2008) showed that young BALB/c mice immunised with a Salmonella bivalent vaccine developed crossprotective immunity against clinical isolates of salmonella (from humans and farm animals) whereas nonvaccinated mice died 21 days post-infection. In aged C57BL/6 mice, there was a 10-fold increase in the number of bacteria in the spleen compared to young mice and early death of infected aged animals.…”