Distinct Effector Memory CD4+ T Cell Signatures in Latent Mycobacterium tuberculosis Infection, BCG Vaccination and Clinically Resolved Tuberculosis

Abstract

Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4+ T cells. However, the differences between long-lived memory CD4+ T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4+ T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-γ ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA−CD27−) antigen-specific effector memory CD4+ T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA−CD27+) cells with low PD-1 expression. CD27+ and CD27− as well as PD-1+ and PD-1− antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-γ, TNF-α and IL-2. PD-1 was preferentially expressed on CD27− antigen-specific CD4+ T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4+ memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27−PD-1+ subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status.

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

“…It will also be interesting to investigate whether this is applicable to young children and for HIVinfected subjects, two patient populations for which TB diagnosis remains particularly difficult [28,29]. Concerning the qualitative differences in immune responses observed between TB disease and LTBI, conflicting findings were previously reported, particularly on the role of IFN-γ + TNF-α + IL-2 + triple positive T cells, which has been proposed as a hallmark of TB disease [30][31][32], as well as of LTBI [33][34][35]. In addition, recent vaccine trials have revealed that these multifunctional triple positive cells not necessarily offer protection in humans [36,37].…”

Lsr2 of Mycobacterium leprae and Its Synthetic Peptides Elicit Restitution of T Cell Responses in Erythema Nodosum Leprosum and Reversal Reactions in Patients with Lepromatous Leprosy

“…The characteristic immunoreactive T cells associated with transient and limited proliferative responses with high levels of IFN-␥ production and cytotoxic function have been linked to a subset of effector memory (T EM ) cells in antigen-primed individuals (32)(33)(34). Repetitive antigen exposure is known to activate T EM cells.…”

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

“…[18][19][20] On the contrary, PD-1 is classically considered a marker of cell exhaustion in the CD8 subset. 21 Thus, the finding of an increased expression of PD-1 in T lymphocytes from CLL patients suggests a relative enrichment in terminally differentiated cells as compared to controls with a similar age.…”