Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain

Abstract

The rise of the AIDS epidemic made the requirement for T cells in our continuous protection from pathogens critically apparent. The striking frequency with which AIDS patients exhibited profound neurological pathologies brought attention to many chronic infections that are latent within the immune-privileged CNS. One of the most common lethal opportunistic infections of these patients was with the protozoan parasite, Toxoplasma gondii. Reactivation of Toxoplasma cysts within the brain causes massive tissue destruction evidenced as multiple ring-enhancing lesions on MRI and is called toxoplasmic encephalitis (TE). TE is not limited to AIDS patients, but rather is a risk for all severely immunocompromised patients, including recipients of chemotherapy or transplant recipients. The lessons learned from these patient populations are supported by T cell depletion studies in mice. Such experiments have demonstrated that CD4+ and CD8+ T cells are required for protection against TE. Although it is clear that these T cell subsets work synergistically to fight infection, much evidence has been generated that suggests CD8+ T cells play a dominant role in protection during chronic toxoplasmosis. In other models of CNS inflammation, such as intracerebral infection with LCMV and experimental autoimmune encephalomyelitis (EAE), infiltration of T cells into the brain is harmful and even fatal. In the brain of the immunocompetent host, the well-regulated T cell response to T. gondii is therefore an ideal model to understand a controlled inflammatory response to CNS infection. This review will examine our current understanding of CD8+ T cells in the CNS during T. gondii infection in regards to the (1) mechanisms governing entry into the brain, (2) cues that dictate behavior within the brain, and (3) the functional and phenotypic properties exhibited by these cells.

Figure 1

A) VLA-4 and VCAM-1 interactions are required for recruitment of CD8+ T cells to brain. Whether interaction between CXCR3 and its ligands governs entry into the parenchyma during chronic toxoplasmosis has not been established, but has been observed in West Nile Virus. Astrocytes and microglia appear to be sources of CXCL9 and CXCL10 during chronic toxoplasmosis. B) Upon entry into the brain CXCR3 ligands help increase the velocity of Levy walks. Interaction between CCR7 and ligands may also govern migration within the parenchyma. For example, CCL21 is expressed on fibrous networks that appear in the brain parenchyma at the chronic stage of infection. C) Antigen recognition with the tissue may also govern long term survival/entry. Microglia, astrocytes, and neurons all express MHC I, but CD8+ T cells have been observed to contact infiltrating DCs during Toxoplasma gondii infection. A percentage of DCs may present antigen through cross presentation, or may be directly infected D) CD8+ T cells contribute to control of reactivation through the actions of IFN-gamma, and control of cyst burden through perforin mediated cell lysis.