Abstract
Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses. Here we report that memory T cell bystander activation is not limited to induction by systemic inflammation. We initially observe potential T cell bystander activation in a cohort of human vaccine recipients. Using a mouse model system, we then find that memory CD8+ T cells are specifically recruited to sites with activated antigen-presenting cells (APCs) in a CXCR3-dependent manner. In addition, CXCR3 is also necessary for T cell clustering around APCs and T cell bystander activation, which temporospatially overlaps with the subsequent antigen-specific T cell response. Our data thus suggest that bystander activation is part of the initial localized immune response, and is mediated by a site-specific recruitment process of memory T cells.
Highlights
Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses
We analyzed the activation profile of human immune cells isolated from peripheral blood mononuclear cells (PBMCs) immediately prior to and 3 days after intra-muscular (i.m.) immunization with a modified vaccinia Ankara (MVA) vector using samples of the human immunodeficiency virus (HIV) Vaccine Trial Network (HVTN) 908 clinical trial (Supplementary Fig. 1a, b)[19,20]
We found that memory (CD45RO+) CD8+ T cells displayed significantly increased median fluorescence intensities (MedFI) for granzyme B in MVA/HIV62 but not placebo recipients (Supplementary Fig. 1c–e)
Summary
Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses. Direct target cell killing depends on NKG2D (expressed on memory T cells)—NKG2D ligand (a family of stress-induced proteins) interactions, which was first demonstrated in a mouse model system[7] and more recently shown using human T cells[3] This innate-like recognition of target cells does not appear to be nearly as efficient as T cell receptor (TCR)mediated target cell killing[7], but the consequences for the host are still significant given the large number of memory T cells and their ability to produce other effector molecules such as IFNγ2,7,10,15,16. Bystander-activated T cells have been shown to drive pathogenesis in the context of chronic infections[10,14,15]
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