Antigen-specific CD8(+) T cells and protective immunity to tuberculosis

Abstract

The continuing HIV/AIDS epidemic and the spread of multi-drug resistant Mycobacterium tuberculosis has led to the perpetuation of the worldwide tuberculosis epidemic. While M. bovis BCG is widely used as a vaccine, it lacks efficacy in preventing pulmonary tuberculosis in adults [1]. To combat this ongoing scourge, vaccine development for tuberculosis is a global priority. Most infected individuals develop long-lived protective immunity, which controls and contains M. tuberculosis in a T cell-dependent manner. An effective T cells response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions, and evaluating whether vaccination can elicit these T cells subsets and induce protective immunity. CD4(+) T cells are critical for resistance to M. tuberculosis in both humans and rodent models. CD4(+) T cells are required to control the initial infection as well as to prevent recrudescence in both humans and mice [2]. While it is generally accepted that class II MHC-restricted CD4(+) T cells are essential for immunity to tuberculosis, M. tuberculosis infection elicits CD8(+) T cells responses in both people and in experimental animals. CD8(+) T cells are also recruited to the lung during M. tuberculosis infection and are found in the granulomas of infected people. Thus, how CD8(+) T cells contribute to overall immunity to tuberculosis and whether antigens recognized by CD8(+) T cells would enhance the efficacy of vaccine strategies continue to be important questions.

Fig. 1

Antigen presentation pathways in infected APC. Mycobacterial peptides can be loaded onto class II MHC within the endocytic pathway. How mycobacterial peptides enter the class I MHC pathway is unknown. One possibility is that (a) the bacterium can translocate from the phagosome and enter the cytosol. Its secreted products could then be processed by the proteasome and the peptide products transported into the ER by the TAP proteins. Alternately, a bacterial secretion system, such as ESX-1, might actively transport secreted proteins across the phagosomal membrane (b). Another possibility is that host machinery, such as sec61, which performs retrograde translocation of proteins, could transport bacterial proteins into the cytosol (C)

Fig. 2

Mechanisms of target cell lysis by CD8⁺ T cells