Resident Th1-like effector memory cells in pulmonary recall responses to Mycobacterium tuberculosis.
We recently described a model of Th1 recall responses based on segmental antigen challenge with purified protein derivative of Mycobacterium tuberculosis (PPD). Bronchoscopic instillation of 0.5 tuberculin units of PPD resulted in localized lymphocytic inflammation in PPD-positive subjects only. Recruited lymphocytes were predominantly CD4+ and were enriched for cells capable of PPD-specific interferon (IFN)-gamma production. In the current study, we investigated the mechanisms by which this localized recall response is mobilized. Bronchoscopic PPD challenge of skin test-positive subjects resulted in the production of CXCR3 ligands IFN-gamma-inducible protein (IP)-10 and monokine induced by IFN-gamma (Mig), but not of CCR5 ligands macrophage inflammatory protein-1alpha and regulated-upon activation, normal T-cell expressed and secreted, whereas skin test-negative subjects produced none of these chemokines. Baseline bronchoalveolar lavage (BAL) cells of skin test-positive subjects produced IP-10 and Mig in response to in vitro stimulation as well. Because IP-10 and Mig are IFN-gamma-inducible chemokines, these findings suggested that chemokine responses to PPD were facilitated by resident memory cells of the lung. Further studies confirmed that baseline BAL lymphocytes of PPD-positive subjects produce IFN-gamma in response to PPD, and that, compared with peripheral blood, BAL cells are preferentially enriched for PPD-specific lymphocytes. This IFN-gamma production is predominantly a function of CD4+ T cells that display the CD45RO+/CCR7- surface phenotype characteristic of effector memory cells.
Walrath
Jessica
J
Division of Pulmonary and Critical Care Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, OH 44106-4984, USA.
Zukowski
Lynn
L
Krywiak
Adriana
A
Silver
Richard F
RF
D000293:Adolescent; D000328:Adult; D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D016131:Lymphocyte Subsets / Q000276:immunology; D008214:Lymphocytes / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010641:Phenotype; D019713:Receptors, CCR5 / Q000378:metabolism; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism* / Q000502:physiology; D014373:Tuberculin / Q000378:metabolism
C515370:CCR7 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014373:Tuberculin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens