Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis

Abstract

Summary CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet, to-date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb infected-mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons; Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection.

The generation of T‐cell memory to protect against tuberculosis

“…These findings parallel those with CD8 + T cells, in which chronic viral infection appears to favor the generation of effector CD8 + T cells, which fail to acquire the key properties of memory cells . Indeed, more recent analysis of antigen‐specific responses revealed that chronic M. tuberculosis infection led to functional exhaustion of CD4 + T cells in mice and humans . Conversely, limited antigen expression correlates with poor T‐cell expansion and poorly persistent live vaccines display limited protection against M. tuberculosis infection in mice .…”

“…Delayed priming of M. tuberculosis ‐specific T cells in the lungs of infected mice has been reported and this presumably contributes to the chronic nature of M. tuberculosis infection. Antigen load is the key determinant in the priming of CD8 + T cells after encounter with mycobacteria and more recent data demonstrate that the abundance and duration of antigen expression defines the function of CD4 + T cells in mice and humans . This further highlights the complexity of TB vaccine design, as the selection of stage‐specific antigens would be required to provide protection during active and/or chronic phases of infection.…”

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

“…This mechanism is functionally important, since an M. tuberculosis strain engineered to express Ag85B throughout infection is attenuated in mice, but only in the presence of CD4 T cells (Bold et al, 2011). However, the findings with Ag85B cannot be extrapolated to all M. tuberculosis antigens, since expression of ESAT-6 is maintained throughout infection, and ESAT-6-spe-cific CD4 T cells can be activated at comparable levels during early and later stages of infection (Moguche et al, 2017). These results emphasize that vaccine antigens must be selected with specific knowledge of their expression dynamics.…”

“…Terminally differentiated (KLRG1 hi CX3CR1 hi T-bet hi ) CD4 T cells confer little protection when adoptively transferred, despite producing larger quantities of IFNγ than less-differentiated (CXCR3 + CX3CR1 − PD-1 hi CD69 hi ) CD4 T cells that traffic to the lung parenchyma and provide protection (Sakai et al, 2014). Terminal differentiation is antigen dependent: ESAT-6-specific CD4 T cells exhibit this property, but Ag85B-specific CD4 T cells do not, since Ag85B expression is reduced in chronic infection (Moguche et al, 2017). T cells with similar properties are present in humans: a vaccine that contains ESAT-6 was found to expand CD4 T cells with limited functional capacities when administered to subjects with LTBI (Moguche et al, 2017).…”

“…Terminal differentiation is antigen dependent: ESAT-6-specific CD4 T cells exhibit this property, but Ag85B-specific CD4 T cells do not, since Ag85B expression is reduced in chronic infection (Moguche et al, 2017). T cells with similar properties are present in humans: a vaccine that contains ESAT-6 was found to expand CD4 T cells with limited functional capacities when administered to subjects with LTBI (Moguche et al, 2017). This finding has important implications, since TB vaccines administered to those that already have LTBI will have little efficacy if they expand poorly functional antigen-specific T cells.…”