A Subset of Circulating Blood Mycobacteria-Specific CD4 T Cells Can Predict the Time to Mycobacterium tuberculosis Sputum Culture Conversion

Abstract

We investigated 18 HIV-negative patients with MDR-TB for M. tuberculosis (Mtb)- and PPD-specific CD4 T cell responses and followed them over 6 months of drug therapy. Twelve of these patients were sputum culture (SC) positive and six patients were SC negative upon enrollment. Our aim was to identify a subset of mycobacteria-specific CD4 T cells that would predict time to culture conversion. The total frequency of mycobacteria-specific CD4 T cells at baseline could not distinguish patients showing positive or negative SC. However, a greater proportion of late-differentiated (LD) Mtb- and PPD-specific memory CD4 T cells was found in SC positive patients than in those who were SC negative (p = 0.004 and p = 0.0012, respectively). Similarly, a higher co-expression of HLA-DR+Ki67+ on Mtb- and PPD-specific CD4 T cells could also discriminate between sputum SC positive versus SC negative (p = 0.004 and p = 0.001, respectively). Receiver operating characteristic (ROC) analysis revealed that baseline levels of Ki67+HLA-DR+ Mtb- and PPD-specific CD4 T cells were predictive of the time to sputum culture conversion, with area-under-the-curve of 0.8 (p = 0.027). Upon treatment, there was a significant decline of these Ki67+HLA-DR+ T cell populations in the first 2 months, with a progressive increase in mycobacteria-specific polyfunctional IFNγ+IL2+TNFα+ CD4 T cells over 6 months. Thus, a subset of activated and proliferating mycobacterial-specific CD4 T cells (Ki67+HLA-DR+) may provide a valuable marker in peripheral blood that predicts time to sputum culture conversion in TB patients at the start of treatment.

Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

“…The presence of CD4 + IFN-γ + T cells in PBMCs from both ATB and LTBI groups was assessed by flow cytometry and intracellular to more rapidly identify delayed responsiveness or nonresponsiveness to anti-TB treatment (e.g., in patients infected with drug-resistant strains) compared with sputum culture and may predict sputum conversion. In this regard, it has recently been suggested that the coexpression of HLA-DR + Ki-67 + on Mtb and purified protein derivative-specific (PPD-specific) CD4 + T cells predicts the time of sputum culture conversion in patients with MDR-TB (48). Notably, CD38…”

Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis

“…Animals vaccinated with MtbΔ sigH displayed higher frequencies of Mtb cell wall- and culture filtrate protein-responsive polyfunctional CD4 + T cells compared with unvaccinated animals. Recent data have shown that markers of T-cell immune activation in human TB are associated with smear and culture conversion during anti-TB treatment 58 . Nonetheless, the current study had some limitations; for example, protection was only demonstrated in a homologous strain.…”

T cells and adaptive immunity to Mycobacterium tuberculosis in humans

“…By contrast, persons with latent infection exhibit higher frequencies of trifunctional IFN‐γ + TNF + IL‐2 + M. tuberculosis ‐specific CD4 + T cells . Furthermore, TB treatment appears to drive the CD4 + T‐cell compartment to a more trifunctional IFN‐γ + TNF + IL‐2 + state . Other studies, however, have found that active TB disease is accompanied by an expansion in the frequency of TNF + IFN‐γ + IL‐2 + CD4 + T cells, as compared to latent infection or to after TB treatment .…”