Bystander T Cells: A Balancing Act of Friends and Foes

T cell responses are essential for appropriate protection against pathogens. T cell immunity is achieved through the ability to discriminate between foreign and self-molecules, and this relies heavily on stringent T cell receptor (TCR) specificity. Recently, bystander activated T lymphocytes, that are specific for unrelated epitopes during an antigen-specific response, have been implicated in diverse diseases. Numerous infection models have challenged the classic dogma of T cell activation as being solely dependent on TCR and major histocompatibility complex (MHC) interactions, indicating an unappreciated role for pathogen-associated receptors on T cells. We discuss here the specific roles of bystander activated T cells in pathogenesis, shedding light on the ability of these cells to modulate disease severity independently from TCR recognition. T cell activation independent of TCR signaling (bystander activation) can be beneficial but also detrimental to the host, as in certain microbial infections. It is driven by T cell-intrinsic expression of pattern-recognition receptors and other costimulatory signals. Bystander activation of T cells has been associated with the exacerbation of disease symptoms for several infections including Borrelia burgdorferi (Lyme disease), Leishmania major (Leishmaniasis), HIV, hepatitis A virus, and Epstein–Barr virus, and others. TCR-independent activation may be beneficial in the context of cancer immunotherapy, where bystander T cells might promote antitumor responses. Present studies aim to better elucidate these pathways.