Lymph node CD8+ T cells cannot effectively prevent HIV rebound after therapy interruption

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Numerous lines of evidence indicate that CD8+ T cells in the blood and vascular spaces (including spleen) can differentiate into cytotoxic subsets capable of rapid target cell killing. This is the classical view of cytotoxic T cell function, and likely what enables cytotoxic T cells to be so effective at eliminating virally infected cells and cancer cells. However, cytotoxic effector differentiated CD8+ T cells lose expression of receptors necessary for entering lymph nodes and non-lymphoid tissues. In contrast, earlier differentiated CD8+ T cells and resident memory CD8+ T cells, primarily capable of cytokine production, appear to have limited direct killing ability (though this can change in response to inflammation or other queues). We hypothesize that tissue intrinsic mechanisms, such as regulatory T cell activity, actively prevent CD8+ T cell cytotoxic effector differentiation as a protective mechanism against host cell damage. Chronic viruses, such as HIV and herpes virus family members, take advantage of this anatomical division, allowing them to form tissue reservoirs and prevent immunological clearance. This study highlights this issue, and points directly to the need to develop alternative strategies to engage cytotoxic mechanisms within these repressive tissue environments.

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