Region of difference 1 antigen-specific CD4+ memory T cells correlate with a favorable outcome of tuberculosis.
BACKGROUND
Interferon (IFN)-gamma response to region of difference (RD) 1 proteins (culture filtrate 10 and early secreted antigenic target 6) or overlapping peptides is a novel diagnostic marker of tuberculosis (TB) infection. Because we have recently shown that the response to certain peptides selected from RD1 allows discrimination between active TB (A-TB) and successfully treated TB (T-TB), we analyzed here the effector memory T cell profile and RD1-specific responses under the same clinical conditions.


METHODS
T cell responses to RD1 antigens were analyzed in patients with either severe or mild A-TB (classified on the basis of radiological lesions) and in 2 sets of healthy control subjects--those who had been successfully treated (the T-TB control subjects) and those whose tuberculin skin test (TST) results were negative (the TST-negative control subjects). IFN-gamma -producing CD4+ effector T cells were monitored by flow-cytometric analysis and ex vivo enzyme-linked immunospot (ELISPOT) assay, whereas a "cultured" ELISPOT assay was used to determine the frequency of memory T cells.


RESULTS
In the patients with severe A-TB, both CD4-mediated effector memory and central memory responses to the selected RD1 peptides were almost absent, whereas these responses were found in the majority of the patients with mild A-TB. In contrast, recognition of the selected RD1 peptides was detected in the T-TB control subjects only by expanding the central memory T cell pool.


CONCLUSIONS
These data suggest a protective role for RD1 peptide-specific CD4+ effector T cells, which undergo clonal expansion during Mycobacterium tuberculosis replication and then a contraction phase after disease resolution, culminating in the generation of CD4+ memory T cells.
Goletti
Delia
D
Second Division of Infectious Diseases of the Health Department, Department of Experimental Research, National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy. d.goletti@tiscali.it
Butera
Ornella
O
Bizzoni
Federica
F
Casetti
Rita
R
Girardi
Enrico
E
Poccia
Fabrizio
F
D000328:Adult; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008297:Male; D009169:Mycobacterium tuberculosis / Q000502:physiology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D011379:Prognosis; D012720:Severity of Illness Index; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D010455:Peptides