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Resident Th1-Like Effector Memory Cells in Pulmonary Recall Responses to Mycobacterium tuberculosis

Divisions of Pulmonary and Critical Care Medicine and Infectious Diseases, Case Western Reserve University School of Medicine; University Hospitals of Cleveland; and Louis B. Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Richard F. Silver, Division of Pulmonary and Critical Care Medicine, Biomedical Research Building, Rm. 1030, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4984. E-mail: rfs4{at}po.cwru.edu

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)- 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-–inducible protein (IP)-10 and monokine induced by IFN- (Mig), but not of CCR5 ligands macrophage inflammatory protein-1 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-–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- in response to PPD, and that, compared with peripheral blood, BAL cells are preferentially enriched for PPD-specific lymphocytes. This IFN- production is predominantly a function of CD4+ T cells that display the CD45RO+/CCR7– surface phenotype characteristic of effector memory cells.

Key Words: chemokines • recall responses • resident memory cells • tuberculosis

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