Objectives: CD4(+)CXCR5(+) T cells have previously been established. However, their decreased frequency during tuberculosis (TB) disease is only partially understood. The aim of this study was to explore the depletion of CD4(+)CXCR5(+) T cells in human TB. Methods: The frequency and function of CD4(+)CXCR5(+) T cells were evaluated in active TB (ATB) patients and healthy control subjects. The function of CD4(+)CXCR5(+) T cells was determined after blockade of inhibitory receptors. Results: The frequency of CD4(+)CXCR5(+) T cells was decreased in ATB patients. The expression of activation markers (HLA-DR and ICOS) and inhibitory receptors (Tim-3 and PD-1) on CD4(+)CXCR5(+) T cells was increased in the ATB group. TB-specific antigen stimulation induced higher expression of inhibitory receptors than phytohemagglutinin stimulation in the ATB group. In contrast, TB antigen stimulation did not induce a significantly increased expression of IL-21 and Ki-67 on CD4(+)CXCR5(+) T cells. However, blockade of inhibitory receptors Tim-3 and PD-1 not only increased the frequency of CD4(+)CXCR5(+) T cells, but also restored their proliferation and cytokine secretion potential. Conclusions: The increased expression of inhibitory receptors involves the depletion of CD4(+)CXCR5(+) T cells, and blockade of inhibitory receptors can restore the function of CD4(+)CXCR5(+) T cells in ATB patients. (c) 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.