Mycobacterium tuberculosis impairs human memory CD4+ T cell recognition of M2 but not M1-like macrophages

Abstract

Direct recognition of Mycobacterium tuberculosis (Mtb)-infected cells is required for protection by CD4+ Tcells. While impaired Tcell recognition of Mtb-infected macrophages was demonstrated in mice, data are lacking for humans. Using Tcells and monocyte-derived macrophages (MDMs) from individuals with latent Mtb infection (LTBI), we quantified the frequency of memory CD4+ Tcell activation in response to autologous MDMs infected with virulent Mtb. We observed robust Tcell activation in response to Mtb infection of M1-like macrophages differentiated using GM-CSF, while M2-like macrophages differentiated using M-CSF were poorly recognized. However, non-infected GM-CSF and M-CSF MDMs loaded with exogenous antigens elicited similar CD4+ Tcell activation. IL-10 was preferentially secreted by infected M-CSF MDMs, and neutralization improved Tcell activation. These results suggest that preferential infection of macrophages with an M2-like phenotype limits Tcell-mediated protection against Mtb. Vaccine development should focus on Tcell recognition of Mtb-infected macrophages.