Viral Modulation of T-Cell Receptor Signaling
Keith R. Jerome



To successfully replicate and spread, viruses must take control of multiple cellular processes. Depending on the cell type infected, a virus may drive cellular differentiation, alter cell cycle progression, or inhibit apoptotic pathways to facilitate viral genomic replication and production of progeny virus. In addition, viruses must deal with an inherently hostile environment in the host. Infection induces intracellular antiviral responses; in addition, the immune system seeks to neutralize virus infectivity and destroy infected cells. Among the cells of the immune system, T lymphocytes (T cells) are critically important for the orchestration of the antiviral response and also for the direct killing of infected cells.
The T-cell receptor (TcR) is the central signaling pathway regulating T-cell biology. The TcR allows the T cell to recognize antigen presented in the context of major histocompatibility complex (MHC) class I or class II molecules expressed on infected cells or professional antigen-presenting cells. TcR signaling in naive T cells drives their activation and expansion. In effector or memory T cells, TcR signaling drives expansion and triggering of effector functions, such as cytokine synthesis and cytotoxicity.

Since T cells pose a threat to the successful replication of viruses, and since TcR signaling is central to the development and function of T cells, it is not surprising that many viruses have evolved mechanisms to modulate TcR signaling. For T lymphotropic viruses, the T cell itself is the major site of viral infection and replication; thus, the virus may stimulate TcR signaling to drive T-cell proliferation such that the T cell is permissive for viral replication. For other viruses, which predominantly infect nonlymphoid cells, the ability to modulate TcR signaling constitutes an immune evasion mechanism, in which the virus inhibits the ability of T cells to respond to infected cells.

As outlined in this review, many viruses modulate TcR function, either positively or negatively, to further their own propagation. However, the specific mechanisms used by each virus to modulate TcR signaling vary widely. Viruses are fascinating in their diversity, and their millennia of evolutionary probing for control points in TcR signaling can educate us regarding the normal function and regulation of this critical pathway.


FIG. 1. TcR signaling. Major activation pathways are depicted by bold green lines, major regulatory mechanisms are depicted by thin red (inhibitory) or green (stimulatory) lines, and alternative LAT-independent TcR signaling is depicted by the dashed green line.

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