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 Mycobacterium tuberculosis is largely determined by the host immune response; therefore, we studied several clinically defined groups of individuals (n = 120) that differ in their ability to contain the bacillus. To quantitate M. tuberculosis-specific T cells directly ex vivo, we enumerated IFN-gamma-secreting CD4 T cells specific for ESAT-6, a secreted Ag that is highly specific for M. tuberculosis, and a target of protective immune responses in animal models. We found that frequencies of circulating ESAT-6 peptide-specific IFN-gamma-secreting CD4 T cells were higher in latently infected healthy contacts and subjects with minimal disease and low bacterial burdens than in patients with culture-positive active pulmonary tuberculosis (p = 0.009 and p = 0.002, respectively). Importantly, the frequency of these Ag-specific CD4 T cells fell progressively in all groups with treatment (p = 0.005), suggesting that the lower responses in patients with more extensive disease were not due to tuberculosis-induced immune suppression. This population of M. tuberculosis Ag-specific Th1-type CD4 T cells appears to correlate with clinical phenotype and declines during successful therapy; these features are consistent with a role for these T cells in the containment of M. tuberculosis in vivo. Such findings may assist in the design and evaluation of novel tuberculosis vaccine candidates.
Pathan
A A
AA
Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Wilkinson
K A
KA
Klenerman
P
P
McShane
H
H
Davidson
R N
RN
Pasvol
G
G
Hill
A V
AV
Lalvani
A
A
D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016764:Cell Polarity; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006683:HLA-DQ Antigens / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D007371:Interferon-gamma