Th1 cytokines, true functional signatures for protective immunity against TB?

Abstract

The lack of an effective preventative vaccine against tuberculosis (TB) presents a great challenge to TB control. Since it takes an extremely long time to accurately determine the protective efficacy of TB vaccines, there is a great need to identify the surrogate signatures of protection to facilitate vaccine development. Unfortunately, antigen-specific Th1 cytokines that are currently used to evaluate the protective efficacy of the TB vaccine, do not align with the protection and failure of TB vaccine candidates in clinical trials. In this review, we discuss the limitation of current Th1 cytokines as surrogates of protection and address the potential elements that should be considered to finalize the true functional signatures of protective immunity against TB.

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…Extending from children to adults, double positive TNF-α+/IFN-γ+ CD4+ T cells and single positive TNF-α+ CD4+ T cells were substantially elevated in active compared to latent TB (101,102). One possible explanation for this complexity is that the timing of Mtb-specific CD4+ T cell responses may be critical to their role in TB protection or burden as in whether the cell population and subsequent inflammation expands before or after Mtb infection (25,103). Thus, pre-existing T cell responses induced by vaccination and or exposure may protect against disease, but expansion of T cells in the context of disease progression may not be helpful.…”

“…Further, we discuss antibody characteristics described in the limited studies of Mtb comorbidity cohorts. Understanding antibody characteristics in Mtb infection, conditions where TB reactivates and their comorbidities will assist in drawing links between immune states in each disease and potential common mechanisms of TB reactivation (25). We speculate whether these antibody characteristics may ultimately find utility as biomarkers in assessing a patient's real-time risk of TB reactivation to personalize treatment plans and follow-up.…”

“…In recent years, there has been more focus on investigating the role of antibodies and innate cells in TB infection and disease (24,25). This interest in humoral immunity in Mtb is evidenced by a mounting number of studies that have identified specific antibody targets, and structural or functional differences that are observed during different TB disease states (26)(27)(28)(29)(30).…”

Towards new TB vaccines

“…Individuals who are CD4+ T cell deficient, such as those infected with HIV, or those with inborn genetic errors of IFNɣ signalling are highly susceptible to M. tuberculosis, thus indicating the importance of the Th1 response [133][134][135]. Whilst essential to controlling M. tuberculosis infection, IFN-ɣ may not be sufficient [136]. Deficiency in other factors such as IL-1, IL-6 and TNFα is also important for protection in murine and human studies [136].…”

“…Whilst essential to controlling M. tuberculosis infection, IFN-ɣ may not be sufficient [136]. Deficiency in other factors such as IL-1, IL-6 and TNFα is also important for protection in murine and human studies [136].…”