Different microbes have developed diverse mechanisms to resist T lymphocyte–mediated host defense (Fig. 1). Many intracellular bacteria, such as Mycobacterium tuberculosis, Legionella pneumophila, and Listeria monocytogenes, inhibit the fusion of phagosomes with lysosomes or create pores in phagosome membranes, allowing these organisms to escape into the cytosol. Thus, these microbes are able to resist the microbicidal mechanisms of phagocytes and survive and even replicate inside phagocytes. Many viruses inhibit class I MHC–associated antigen presentation by inhibiting production or expression of class I molecules, by blocking transport of antigenic peptides from the cytosol into the endoplasmic reticulum (ER) and by removing newly synthesized class I molecules from the ER. All these viral mechanisms reduce the loading of class I MHC molecules by viral peptides. The result of this defective loading is reduced surface expression of class I MHC molecules, because empty class I molecules are unstable and are not expressed on the cell surface. It is interesting that NK cells are activated by class I–deficient cells . Thus, host defenses have evolved to combat immune evasion mechanisms of microbes: CTLs recognize class I MHC–associated viral peptides, viruses inhibit class I MHC expression, and NK cells recognize the absence of class I MHC molecules on infected or stressed cells.

Fig1. Evasion of cell-mediated immunity (CMI) by microbes. Select examples of different mechanisms by which bacteria and viruses resist the effector mechanisms of CMI. CTL, Cytotoxic T lymphocyte; ER, endoplasmic reticulum; IFN, interferon; IL, interleukin; TAP, transporter associated with antigen processing.

Other viruses produce inhibitory cytokines or soluble (decoy) cytokine receptors that bind and neutralize cytokines such as IFN-γ, reducing the amount of cytokines available to trigger cell-mediated immune reactions. Some viruses evade elimination and establish chronic infections by stimulating expression of inhibitory receptors, including PD-1 (programmed [cell] death protein 1) on CD8+ T cells, thus inhibiting the effector functions of CTLs. This phenomenon, in which the T cells mount an initial response against the virus but the response is pre maturely terminated, has been called T cell exhaustion (Fig. 2). It typically occurs as a reaction to chronic antigenic stimulation, as in chronic viral infections or tumors, and is a mechanism by which the repeatedly stimulated T cell terminates its own response. Still other viruses directly infect and kill immune cells, the best example being human immunodeficiency virus (HIV), which is able to survive in infected persons by killing CD4+ T cells.

Fig2. T cell activation and exhaustion. A, In an acute viral infection, virus-specific CD8+ T cells proliferate, differentiate into effector CTLs and memory cells, and clear the virus. B, In some chronic viral infections, CD8+ T cells mount an initial response but begin to express inhibitory receptors (such as PD-1 and CTLA-4) and are inactivated, leading to persistence of the virus. This process is called exhaustion because the T cells do make a response, but this is short lived.

The outcome of infections is influenced by the strength of host defenses and the ability of pathogens to resist these defenses. The same principle is evident when the effector mechanisms of humoral immunity are considered. One approach for tilting the balance between the host and microbes in favor of protective immunity is to vaccinate individuals to enhance adaptive immune responses.

Tumors, like infectious pathogens, have developed several mechanisms for evading or resisting CD8+ T cell–mediated immunity. These mechanisms include inhibiting expression of class I MHC molecules and inducing T cell exhaustion. Blocking some of these evasion mechanisms provides effective strategies for unleashing antitumor immunity .