Dynamic Relationship between IFN-γ and IL-2 Profile of Mycobacterium tuberculosis-Specific T Cells and Antigen Load

Abstract

Distinct IFN-gamma and IL-2 profiles of antigen-specific CD4+ T cells have recently been associated with different clinical disease states and antigen loads in viral infections. We assessed the kinetics and functional profile of Mycobacterium tuberculosis antigen-specific T cells secreting IFN-gamma and IL-2 in 23 patients with untreated active tuberculosis, when bacterial and antigen load are high, and after curative treatment when antigen load is reduced. Frequencies of M. tuberculosis antigen-specific IFN-gamma-secreting T cells declined during 28 months of follow up with an average percentage decline of 5.8% per year (P=0.005), whilst frequencies of antigen-specific IL-2-secreting T cells increased during treatment (P=0.02). These contrasting dynamics for the two cytokines led to a progressive convergence of the frequencies of IFN-gamma and IL-2-secreting cells over 28 months. Simultaneous measurement of IFN-gamma and IL-2 secretion at the single cell level revealed a co-dominance of IFN-gamma-only and IFN-gamma/IL-2 dual-secreting CD4+ T cells in active disease which shifted to dominance of IFN-gamma/IL-2-secreting CD4+ T cells and newly detectable IL-2-only-secreting CD4+ T cells during and after treatment. These distinct T cell functional signatures before and after treatment suggest a novel immunological marker of mycobacterial load and clinical status in tuberculosis, which now requires validation in larger prospective studies.

LTBI: latent tuberculosis infection or lasting immune responses toM. tuberculosis? A TBNET consensus statement

“…In contrast, long-lived central memory T-cells that may persist even after successful treatment of tuberculosis [11,12,36,37,56,57] are less likely to release IFN-c after ,24 h of incubation and more likely to produce IL-2 [56].…”

“…Consequently, novel concepts have been investigated that include the use of different epitopes of RD antigens [11,12,36,37,58], readout different from IFN-c such as chemokines or cytokines [56,58], new antigens different from the RD genomic region, such as those defined as Rv1733c, Rv2029c, Rv2032, Rv2626c, Rv2627c, Rv2628 and HspX [29,[59][60][61], additional cytokines [56] or characteristic phenotypic markers [11,12,36,62]. Diagnostic sensitivity of IGRA can also be enhanced by incorporation of a novel RD1-encoded antigen, Rv3879c, without compromising diagnostic specificity [63].…”

Polyfunctional T cells in human tuberculosis

“…Therefore MTB-specific CD4 1 T cells secreting IL-2 alone or in combination with other cytokines could be potential correlates of MTB protection. Treatment of MTB in HIVuninfected TB patients leads to a shift from predominantly IFN-g single positive CD4 1 T cells to predominantly IFN-g 1 /IL-2 1 and newly detectable IL-2 single positive T cells [15]. Together with data derived from mouse models of Leishmania and TB [16,17], the above studies suggest that polyfunctional T cells may be associated with protection against intracellular pathogens in general, not just viruses; however, it is important to point out that none of the above studies provided direct evidence that these polyfunctional T cells are associated with protection, for example by comparing patients who do or do not have active TB disease.…”

Cellular immune parameters associated with spontaneous control of CMV in children who underwent transplantation

“…Specifically, fully functional memory CD4 þ T cells that can secrete IL-2 in addition to IFNg rather than effector/memory CD4 þ T cells that secrete IFNg alone seem to be associated with a lower incidence of disease in various infections. [11][12][13][14][15][16] To obtain a further insight into the developmental kinetics of fully functional memory cells, in this study, we addressed the relationship between CMV control and the development of proliferative responses by CD4 þ T cells. In vitro proliferative responses to a CMV-lysate antigenic preparation were selected, instead of IL-2 secretion, for two reasons.…”