Is Infant Immunity Actively Suppressed or Immature?

Abstract

Almost 7 million children under the age 5 die each year, and most of these deaths are attributable to vaccine-preventable infections. Young infants respond poorly to infections and vaccines. In particular, dendritic cells secrete less IL-12 and IL-18, CD8^pos T cells and NK cells have defective cytolysis and cytokine production, and CD4^pos T cell responses tend to bias towards a Th2 phenotype and promotion of regulatory T cells (T_regs). The basis for these differences is not well understood and may be in part explained by epigenetic differences, as well as immaturity of the infant's immune system. Here we present a third possibility, which involves active suppression by immune regulatory cells and place in context the immune suppressive pathways of mesenchymal stromal cells (MSC), myeloid-derived suppressor cells (MDSC), CD5^pos B cells, and T_regs. The immune pathways that these immune regulatory cells inhibit are similar to those that are defective in the infant. Therefore, the immune deficiencies seen in infants could be explained, in part, by active suppressive cells, indicating potential new avenues for intervention.

Keywords: immune suppression; infant immunity; infant vaccines.

Figure 1

Known characteristics of the infant’s immune responses. A. Immaturity of the infant’s immune system is dictated by the inability of inflammatory dendritic cells (inf APC) to produce IL-12 and IL-18. This leads to an impaired CD8+ T cell, NK cell and Th1 responses upon stimulation. The T-helper response is skewed toward Th2. The decreased ability of inf APC to effectively prime T helper responses leads to a decreased ability to provide the needed help for strong T dependent B cell responses. B. Possible involvement of specific regulatory cells in shaping the infant’s immune response described in A. Regulatory T cells (Tregs) suppress T cell proliferation and IFN-g secretion. CD5+ B cells decrease IL-12 production by inflammatory dendritic cells and skew the T helper response towards a Th2 phenotype. Myeloid derived suppressor cells (MDSC) suppress T cell proliferative responses, decrease IL-5, IL-17, and IFN-g production, and skew the T cell phenotype towards Th2. MDSC also inhibit IFN-g production by NK cells. Mesenchymal Stromal Cells (MSC) skew the dendritic cell differentiation towards a regulatory phenotype and induce MDSC. This induces the generation of Tregs from Th1 and Th17 cells. MSC induce T cell anergy and suppress NK cell proliferation, cytotoxicity and cytokine production.