Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG). Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4+ T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2) as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4+ T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4+ T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4+ T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4+ T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4+ T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in the immune response against Mtb.

Innovative antigen carrier system for the development of tuberculosis vaccines

“…The cell-mediated immune response was analyzed by measuring the various cytokine releases from splenocytes restimulated with soluble His6-H4 or His6-H28. IFN-g, a T h 1 cytokine strongly associated with cellmediated immune response, has a significant role in protection from TB (56,58). The particulate vaccinesimmunized group showed a higher IFN-g production when compared with the soluble vaccines-immunized group in response to either soluble His6-H4 or His6-H28 stimulation at the later culture time point (Fig.…”

“…Cell-mediated immunity, contributed by T cells, plays an important role for protection against intracellular pathogens (56). Polyfunctional CD4 + T cells could simultaneously produce multiple T h 1 cytokines (IFN-g, IL-2, and TNF-a) after M. tuberculosis infection or vaccination (56)(57)(58). The cell-mediated immune response was analyzed by measuring the various cytokine releases from splenocytes restimulated with soluble His6-H4 or His6-H28.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…While the BCG vaccine protects against disseminated tuberculosis, especially in young children who are most at risk, its ability to protect from pulmonary disease varies across the world 86. Current studies in mice, non‐human primates and humans are focussed on increasing the immune protection offered by BCG, for example by using prime‐boost strategies 86, 87.…”

“…While the BCG vaccine protects against disseminated tuberculosis, especially in young children who are most at risk, its ability to protect from pulmonary disease varies across the world 86. Current studies in mice, non‐human primates and humans are focussed on increasing the immune protection offered by BCG, for example by using prime‐boost strategies 86, 87. BCG effectiveness can also be achieved by altering the vaccination route, with mucosal and intravenous routes offering enhanced protection compared with more traditional subcutaneous or intradermal injection in a non‐human primate model 88.…”

“…86 Current studies in mice, non-human primates and humans are focussed on increasing the immune protection offered by BCG, for example by using prime-boost strategies. 86,87 BCG effectiveness can also be achieved by altering the vaccination route, with mucosal and intravenous routes offering enhanced protection compared with more traditional subcutaneous or intradermal injection in a non-human primate model. 88 Potentially these injection routes provide enhanced protection as they are better at driving the development of CD4 Trm cells in the lung.…”