Th1, Th17, and Th1Th17 Lymphocytes during Tuberculosis: Th1 Lymphocytes Predominate and Appear as Low-Differentiated CXCR3+CCR6+ Cells in the Blood and Highly Differentiated CXCR3+/-CCR6- Cells in the Lungs

Abstract

Th1 lymphocytes are considered the main mediators of protection against tuberculosis (TB); however, their phenotypic characteristics and relationship with Th17 and Th1Th17 populations during TB are poorly understood. We have analyzed Th1, Th17, and Th1Th17 lymphocytes in the blood and pulmonary lesions of TB patients. The populations were identified based on the production of IFN-γ and/or IL-17 and the coexpression of CXCR3 (X3) and CCR6 (R6). In the blood, IL-17⁺ and IFN-γ⁺IL-17⁺ lymphocytes were barely detectable (median, <0.01% of CD4⁺ lymphocytes), whereas IFN-γ⁺ lymphocytes predominated (median, 0.45%). Most IFN-γ⁺ lymphocytes (52%) were X3⁺R6⁺, suggesting their "nonclassical" (ex-Th17) nature. In the lungs, IL-17⁺ and IFN-γ⁺IL-17⁺ lymphocytes were more frequent (0.3%, p < 0.005), yet IFN-γ⁺ cells predominated (11%). Phenotypically, lung CD4⁺ cells were X3^+/loR6^- The degree of differentiation of blood effector CD4⁺ lymphocytes (evaluated based on CD62L/CD27/CD28 coexpression) increased as follows: X3⁺R6⁺ < X3⁺R6^- < X3^-R6^-, with X3^-R6^- cells being largely terminally differentiated CD62L^-CD27^-CD28^- cells. Lung CD4⁺ lymphocytes were highly differentiated, recalling blood X3^+/-R6^- populations. Following in vitro stimulation with anti-CD3/anti-CD28 Abs, X3⁺R6⁺CD4⁺ lymphocytes converted into X3⁺R6^- and X3^-R6^- cells. The results demonstrate that, during active TB, Th1 lymphocytes predominate in blood and lungs, document differences in X3/R6 expression by blood and lung CD4⁺ cells, and link the pattern of X3/R6 expression with the degree of cell differentiation. These findings add to the understanding of immune mechanisms operating during TB and are relevant for the development of better strategies to control it.