Febrile temperature change modulates CD4 T cell differentiation via a TRPV channel-regulated Notch-dependent pathway

Abstract

Fever is a conserved and prominent response to infection. Yet, the issue of how CD4 T cell responses are modulated if they occur at fever temperatures remains poorly addressed. We have examined the priming of naive CD4 T cells in vitro at fever temperatures, and we report notable fever-mediated modulation of their cytokine commitment. When naive CD4 T cells were primed by plate-bound anti-CD3 and anti-CD28 monoclonal antibodies at moderate fever temperature (39 °C), they enhanced commitment to IL4/5/13 (Th2) and away from IFNg (Th1). This was accompanied by up-regulation of the Th2-relevant transcription factor GATA3 and reduction in the Th1-relevant transcription factor Tbet. Fever sensing by CD4 T cells involved transient receptor potential vanilloid cation channels (TRPVs) since TRPV1/TRPV4 antagonism blocked the febrile Th2 switch, while TRPV1 agonists mediated a Th2 switch at 37 °C. The febrile Th2 switch was IL4 independent, but a γ-secretase inhibitor abrogated it, and it was not found in Notch1-null CD4 T cells, identifying the Notch pathway as a major mediator. However, when naive CD4 T cells were primed via antigen and dendritic cells (DCs) at fever temperatures, the Th2 switch was abrogated via increased production of IL12 from DCs at fever temperatures. Thus, immune cells directly sense fever temperatures with likely complex physiological consequences.

Fever supports CD8 + effector T cell responses by promoting mitochondrial translation

“…Innate immune cells primarily drive fever, which in turn can have multiple effects on the adaptive arm of the immune system. For example, fever can induce T cell migration, Th subset polarization, and enhanced cytokine production (2)(3)(4)(5).…”

Exploring the rationale for thermotherapy in COVID-19

“…Dendritic cells (DCs) display increased migration and recruitment to secondary lymphoid organs with improved ability of antigen presentation to naive CD8þ T lymphocytes and increased cytokine production, particularly TNF-a [48]. Under these temperatures, gene expression is modified in DCs, with upregulation of 43 genes and downregulation of 24 genes involved in post-transcriptional modifications, protein folding, cell death/survival, and migration [49], as well as interleukin (IL)-12 production [50], which could bias the immune response toward a Th1 phenotype [51,52]. An early Th1 immune response is important since Th1 cells are able to produce cytokines and recruit innate immune cells [53], which has been associated with rapid viral clearance and mild disease in COVD-19 [54].…”

Immunological Mechanisms of Sickness Behavior in Viral Infection

“…NK cells show increased cytotoxic activity and increased migration to sites of inflammation under conditions of increased body temperature [20]. Finally, CD4 T cells modulate their immunological behavior under conditions of moderate fever by induction of GATA-3 and promoting the secretion of IFNγ, IL-4, and IL-13 [24].…”