Bystander T Cells: A Balancing Act of Friends and Foes

Abstract

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.

Keywords: T cell activation; autoimmunity; bystander; cancer; infection; pathogenesis; signaling.

Figure 1.. Reported Human Anatomical Locations of Infections and Diseases Associated with Bystander T Cell Activation.

Bystander T cells have been implicated in both viral and bacterial infections as well as in various autoimmune and inflammatory diseases.

Figure 2.. Bystander T cell activation during Borrelia burgdorferi infection in humans and mice results in exacerbation of Lyme disease.

Borrelia burgdorferi spirochetes disseminate to the synovial joint resulting in the infiltration of mononuclear cells, including dendritic cells and T cells into the synovial tissue. (1) B. burgdorferi stimulates TLR1/2 signaling through its outer surface lipoproteins (Osps), which results in the secretion of several proinflammatory cytokines including IL-1β, IL-12, IL-6 and T cell chemoattractants CXCL9 and CXCL10. (2) Inflammatory T cell responses concentrated in the joint fluid may become bystander activated cells through TLR1/2 and cytokine receptor signaling (3). Together, cytokine signaling and TLR1/2 signaling within T cells results in the secretion of proinflammatory IFNγ. (4) T cell responses can alter fibroblast-like synoviocytes, leading to synovial pathology including the erosion of bone and cartilage.