Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis

Abstract

Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.

Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

“…Also we report for the first time that trafficking of mouse CD1d and its Ag presentation ability is regulated by phosphatidyl inositol 3-kinase. Although the occurrence of cross-presentation of lipid Ags in vivo is inferred from earlier studies (20,21), the present data further elucidate the intracellular pathways involved in the presentation of exogenous self-glycolipids bound by CD1d to type II NK T cells.…”

Cell death in the host response to infection

“…6 Engulfment of dying macrophages by dendritic cells additionally promotes antigen presentation to T cells, linking innate and adaptive immunity. [7][8][9][10] Apoptosis of alveolar macrophages in Streptococcus pneumoniae infection also results in pathogen elimination rather than evasion of the immune system. 11 Pathogens have devised strategies to inhibit cell death for a successful infection.…”

Optimization of inhaled therapies for tuberculosis: The role of macrophages and dendritic cells

“…In addition, macrophages from an inbred strain of mouse (C3HeB/FeJ) that is susceptible to M. tuberculosis infection undergo necrosis when infected while macrophages from the less susceptible strains of mice undergo apoptosis.96 Furthermore, apoptotic vesicles released by dying, infected macrophages are taken up by dendritic cells and cross prime CD8+ T cells via MHC1 and CD1 molecules. [97] and [98] The resulting antigen-specific cytotoxic T cells can then kill infected macrophages via the perforin-granzyme pathway.…”