Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: Associations with clinical disease state and effect of treatment

The wide spectrum of clinical outcomes following infection with Mycobacteri um tuberculosis is largely determined by the host immune response; therefor e, we studied several clinically defined groups of individuals (n = 120) th at differ in their ability to contain the bacillus. To quantitate Al. tuber culosis-specific T cells directly ex vivo, we enumerated IFN-gamma -secreti ng CD4 T cells specific for ESAT-6, a secreted Ag that is highly specific f or M. tuberculosis, and a target of protective immune responses in animal m odels. We found that frequencies of circulating ESAT-6 peptide-specific IFN -gamma -secreting CD4 T cells were higher in latently infected healthy cont acts and subjects with minimal disease and low bacterial burdens than in pa tients with culture-positive active pulmonary tuberculosis (p = 0.009 and p = 0.002, respectively). Importantly, the frequency of these Ag-specific CD 4 T cells fell progressively in all groups with treatment (p = 0.005), sugg esting that the lower responses in patients with more extensive disease wer e not due to tuberculosis-induced immune suppression. This population of M. tuberculosis Ag-specific Th1-type CD4 T cells appears to correlate with cl inical phenotype and declines during successful therapy; these features are consistent with a role for these T cells in the containment of M. tubercul osis in vivo. Such findings may assist in the design and evaluation of nove l tuberculosis vaccine candidates.