Mycobacterium tuberculosis Impairs Human Memory CD4 T Cell Recognition of Macrophages Differentiated Using M-CSF But Not GM-CSF

Abstract

Direct recognition of Mycobacterium tuberculosis (Mtb) infected cells is required for protection by CD4⁺ T cells. While impaired T cell recognition of Mtb-infected macrophages was demonstrated in mice, data are lacking for humans. Using T cells and monocyte-derived macrophages (MDMs) from individuals with latent Mtb infection (LTBI), we quantified the frequency of memory CD4⁺ T cell activation in response to autologous MDMs infected with virulent Mtb. We observed robust T cell activation in response to Mtb-infection of macrophages differentiated using GM-CSF, while those differentiated using M-CSF were poorly recognized. However, non-infected GM-CSF and M-CSF MDMs loaded with exogenous antigens elicited similar CD4⁺ T cell activation. IL-10 was preferentially secreted by infected M-CSF MDMs, and neutralization improved T cell activation. These results suggest that preferential infection of macrophages with an M2-like phenotype limits T cell-mediated protection against Mtb. Vaccine and therapeutics development should focus on directing T cells to recognize infected cells.

Keywords: Mycobacterium tuberculosis, TB, human, memory, CD4 T cell, recognizing the infected cell, Vaccine, IL-10, GM-CSF, M-CSF, macrophage