Fever is a fundamental response to infection and inflammatory disease. This response is accompanied by innate and adaptive immune responses to confer a survival benefit during infection.

However, most studies of fever-mediated modulation of immune responses address innate immune cells. Little work has been done to elucidate what molecular pathways in the adaptive immune system are involved in the sensing of this rise in temperature.

In a paper published in the August 24, 2020, online issue of the Proceedings of the National Academy of Sciences (PNAS), Satyajit Rath's group from the National Institute of Immunology, India, has examined the effects of fever temperatures on crosstalk between the innate and adaptive immune systems. Their work shows that moderate fever temperatures modified naive CD4 T-cell responses via transient receptor potential cation channel subfamily V (TRPV) channel-mediated pathway involving Notch activation.

Rath is a professor at the National Institute of Immunology, and his research focuses on the physiological control of the generation and activation of T, B and antigen-presenting cells (APCs) of the myeloid lineage, using a variety of interlinked experimental systems and approaches.

"We started with the idea that the everyday realities in poor human communities, such as in the global South, as well as in natural non-human species in their ecosystems, likely involve fairly high frequencies of pathogenic microbial exposure," Rath told BioWorld Science. "That would mean that independent microbial infections would quite commonly overlap, meaning that a new infection would arrive in the body while the body still has the effects of an earlier one.

The commonest body-wide consequence of an infection is, of course, fever. "We set up some simple model systems to understand the cellular physiological consequences of this fevered microenvironment in immune responses, specifically CD4 T-cell responses, to the new infection."

A fine balance

During antigen challenge, CD4 T cells can produce two types of response based on the cytokines they are exposed to. Th1-type cytokines such as interferon-gamma (IFN-gamma) tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses.

Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2-type cytokines include IL-4, IL-5 and IL-13, which are associated with the promotion of immunoglobulin E (IgE), and IL-10, which has more of an anti-inflammatory response. In excess, the Th2 responses counteract the Th1-mediated microbicidal action. Thus, in the physiological context, a well-balanced Th1 and Th2 response is desired, suited to the immune challenge.

In both in vitro and in vivo mouse models, Rath and his colleagues observed that a 1-degree Celsius rise between 38 degrees C and 39 degrees C triggered the differentiation of naive CD4 T cells to generate the Th2 response. This Th2 response was, however, independent of IL-4 production.

Because TRPV is involved in the detection and regulation of body temperature, the researchers wanted to test if TRPV channels were involved in thermosensing during CD4 T-cell differentiation. Of all the subunits, TRPV1 and TRPV4 were seen to play a role in CD4 T-cell thermosensing.

Upregulating TRPV signaling in naive CD4 T cells while priming them at 37 degrees C resulted in simulation of fever temperature by generating a shift towards the Th2 response of the responding CD4 T cells. But there was no change in TRPV expression levels by either T-cell activation or by fever temperature.

Rath said that "it was surprising that a 1-degree Celsius change of temperature could have such major functional consequences for functional cellular programming." Further, the TRPV-mediated signals during febrile temperature ranges induced Notch1 activation, possibly by altering its trafficking during endocytotic recycling, since TRPV channels are known regulators of endocytosis.

In the in vitro models, Rath and his team saw that when antigen-presenting dendritic cells and responding CD4 T cells interacted, as would happen physiologically during a febrile episode, they produced substantial amounts of the cytokine IL-12. Blocking this IL-12 production was enough for fever-mediated Th2 switching to occur. These data indicate that fever temperatures in vivo induce a Th2 switch in responding CD4 T cells, but this outcome is likely to be modulated further by the presence and concentration of IL-12 in the microenvironment.

Overall, the results demonstrated a complex and delicate fine tuning of immune responses during a febrile episode that helped combat infection while aiming to cause the least inflammatory damage.

"In terms of the basic biological mechanisms we have reported, the fine temperature discrimination is an interesting point," Rath said. "But perhaps even more interestingly, our data suggest that this kind of discrimination could be connected to the underlying 'physiological' body temperature, signifying possible complexities in the evolution of these signaling networks. We plan to examine and confirm the molecular basis of fever sensing, the connections between fever sensing and Notch pathway activation, and the in vivo significance of our findings." (Umar, D. et al. Proc Natl Acad Sci U S A 2020, Advanced publication).

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