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Differential Regulation of Primary and Secondary CD8⁺ T Cells in the Central Nervous System¹

Chandran Ramakrishna^*, Stephen A. Stohlman^*,, Roscoe A. Atkinson, David R. Hinton and Cornelia C. Bergmann^2,*,

Departments of ^* Neurology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

T cell accumulation and effector function following CNS infection is limited by a paucity of Ag presentation and inhibitory factors characteristic of the CNS environment. Differential susceptibilities of primary and recall CD8⁺ T cell responses to the inhibitory CNS environment were monitored in naive and CD8⁺ T cell-immune mice challenged with a neurotropic coronavirus. Accelerated virus clearance and limited spread in immunized mice was associated with a rapid and increased CNS influx of virus-specific secondary CD8⁺ T cells. CNS-derived secondary CD8⁺ T cells exhibited increased cytolytic activity and IFN- expression per cell compared with primary CD8⁺ T cells. However, both Ag-specific primary and secondary CD8⁺ T cells demonstrated similar contraction rates. Thus, CNS persistence of increased numbers of secondary CD8⁺ T cells reflected differences in the initial pool size during peak inflammation rather than enhanced survival. Unlike primary CD8⁺ T cells, persisting secondary CD8⁺ T cells retained ex vivo cytolytic activity and expressed high levels of IFN- following Ag stimulation. However, both primary and secondary CD8⁺ T cells exhibited reduced capacity to produce TNF-, differentiating them from effector memory T cells. Activation of primary and secondary CD8⁺ T cells in the same host using adoptive transfers confirmed similar survival, but enhanced and prolonged effector function of secondary CD8⁺ T cells in the CNS. These data suggest that an instructional program intrinsic to T cell differentiation, rather than Ag load or factors in the inflamed CNS, prominently regulate CD8⁺ T cell function.

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