Phenotype and Regulation of Persistent Intracerebral T Cells in Murine Toxoplasma Encephalitis

Abstract

Toxoplasma gondii is a parasite causing asymptomatic, persistent encephalitis. Protective CD4 and CD8 T cells are recruited to and accumulate in the brain in acute Toxoplasma encephalitis (TE), with slowly decreasing numbers in chronic TE. It is unclear how the size of the intracerebral T cell pool is regulated. Conceivably, permanent recruitment, proliferation, and apoptosis may be involved. We observed that in murine TE recruitment of T cells to the brain was terminated in chronic TE. In vivo 5-bromo-2′-deoxyuridine incorporation and in vitro T cell proliferation experiments revealed that intracerebral T cells did not proliferate, which was explained by the expression of the cell cycle inhibitors p21Waf/cip1 and p27Kip1 and the inhibitory activity of intracerebral F4/80+ cells. TUNEL staining detected apoptotic T cells at low frequency corresponding to an increased expression of the anti-apoptotic molecules Bcl-2 and Bcl-xL and a reduced expression of the pro-apoptotic molecules Bad, Bax, and Fas ligand in CD4 and CD8 T cells. During progression from acute to chronic TE, both CD4 and CD8 T cells down-regulated CD45RB expression and expressed a differential pattern of cytokines. From these experiments it is concluded that the number of intracerebral T cells increases by recruitment of T cells during acute infection, whereas proliferation of intracerebral T cells does not play a role. In chronic TE, T cell recruitment is terminated, the phenotype of intracerebral T cells changes, and their number is gradually downsized by low level apoptosis, which, however, does not completely resolve the T cell infiltrates.

The Induction and Kinetics of Antigen-Specific CD8 T Cells Are Defined by the Stage Specificity and Compartmentalization of the Antigen in Murine Toxoplasmosis

“…Thus, intracerebral CD8 T cells specific for a secreted Ag of tachyzoite were not eliminated from the brain in chronic TE, i.e., when the parasite persists as bradyzoites within cysts. The persistence of these CD8 T cells is consistent with the observation that intracerebral T cells form a stable cell pool in chronic TE, which is only slowly downsized by a low level of apoptosis (7). Because ␤-gal-specific CD8 T cells were functionally active and rapidly produced IFN-␥ (the major cytokine in resistance against T. gondii (33)) upon peptide restimulation and also killed peptide-pulsed APCs, they appear to play an important role in the control of intracerebral parasites in acute and chronic TE.…”

“…with PruS1SPLACZ, when a significant number of leukocytes including CD8 T cells had already been recruited to the brain (Ref. 7 and present study, data not shown), 2.0 and 4.2% of total CD8 T cells in the spleen and the brain stained positively with L d /␤-gal 876 -884 tetramer, respectively (Fig. 4, A and B).…”

“…(31,32). Beyond day 23 p.i., the frequency of ␤-gal-specific CD8 T cells dropped rapidly, which may be caused by a fast contraction of the Ag-specific CD8 T cell population in the spleen as well as a recruitment of ␤-gal-specific CD8 T cells to the brain (7). In fact, the formation of intracerebral T cell infiltrates in TE strictly depends on the recruitment of peripheral T cells to the brain.…”

“…In addition, perforin-mediated killing of T. gondii-infected cells by CD8 T cells contributes to parasite control in chronic Toxoplasma encephalitis (TE), during which CD8 T cells represent ϳ30 -50% of all inflammatory leukocytes (6,7). The crucial role of CD8 T cells in the control of T. gondii is further evidenced by immunogenetic studies in mice, which revealed that the MHC class I L d molecule confers protection against toxoplasmosis, although immunodominant MHC class I-restricted epitopes of T. gondii have not yet been identified (8,9).…”

Dynamic Imaging of T Cell-Parasite Interactions in the Brains of Mice Chronically Infected withToxoplasma gondii

“…Given that cytokines could act in a paracrine fashion to stimulate other cell types, such as macrophages and astrocytes, to control T. gondii growth (11-13, 25, 26) it is conceivable that CD8 T cells could provide protection without the need to stably contact invaded host cells. Studies of leukocytes isolated from brains of chronically infected mice have provided important information about CD8 T cells (24,(27)(28)(29); however the nature of interactions between CD8 T cells and brain APCs has not yet been explored.…”