Targeting regulatory T cells to improve vaccine immunogenicity in early life

Abstract

Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future.

Determinants of early life immune responses to RSV infection

“…Immunosuppressive plasma factors such as adenosine and anti-inflammatory cytokines dampen inflammatory responses, and transforming growth factor beta (TGFβ) has been found to mediate suppression of natural killer (NK) cell function. Tregs, one potential source of TGFβ, have been found in higher numbers in newborns and preterm infants and possess immunosuppressive functions during early life [15,16]. Another cellular source of immunosuppression, CD71+ erythroid cells, are prevalent during early life and may compromise host defenses [17].…”

“…FDC express an array of TLRs [51], and TLR ligation could potentiallypromote FDC maturation, help organize and maintain germinal centers, and support the development of high-affinity antibodies.Despite technical hurdles, this is an important area for future investigation. For an infant vaccine, special consideration of the potential of TLR agonists to stimulate Tregs should be given, as different TLR agonists have been shown to preferentially expand effector T cells over Tregs, and vice versa [16]. …”

DNA vaccines, electroporation and their applications in cancer treatment

“…Regulatory T cells are also involved in inhibiting T cell function by many different strategies, but the suppression of these cell populations results in improved vaccine immunogenicity (reviewed in 139 ). Myeloid-derived stem cells are also known to suppress T cell responses and to induce tolerance to cancer-associated antigens (reviewed in 140 ).…”

The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection

“…FOXP3+ T regulatory cells (Tregs) are involved in the regulation of inflammatory processes and exert immunosuppressive functions by cell contact-dependent suppression of CD4+ T cells and by secretion of inhibitory cytokines and soluble factors [5, 6]. Tregs may dampen protective immunity facilitating pathogen multiplication and dissemination [7] and may also limit vaccine immunogenicity [8]. Thus, targeting of Tregs may have potential as host directed adjunctive therapies [9].…”