A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation

Abstract

Abbreviations: APC, antigen-presenting cell; CD28, cluster of differentiation 28; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CTxB, cholera toxin B subunit; Ct, cycle threshold; ELISA, enzyme-linked immunosorbant assay; EtOH, ethanol; FITC, fluoroisothiocyanate; GM1, monosialotetrahexosylganglioside; IDEAS, imagestream data exploration and analysis software; IL-2, interleukin 2; LA, latrunculin A;MbCD, methyl-b-cyclodextrin; PD-1, Programmed cell death-1; PMA, phorbol 12-myristate 13-acetate; pMHC, peptide-major histocompatibility complexes; qRT-PCR, quantitative reverse transcription polymerase chain reaction; TCR, T cell receptor; TDI, time delay integration; TMA-DPH, trimethylammonium diphenylhexatriene; WBH, whole body hyperthermia.Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4C T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4C T cells to become more quickly and easily activated during times of infection during fever.

Fever and the thermal regulation of immunity: the immune system feels the heat

“…151,152 Similar heat-induced changes in membrane fluidity and macromolecular clustering in the plasma membrane occur in CD4 + T cells which reduce the requirement for CD28 stimulation for IL-2 production. 153 These findings suggest that febrile temperatures lower the threshold for T cell signalling and effector T cell differentiation by pre-associating the signalling components of the TCR complex.…”

Immune Cells and Inflammation in Diabetic Nephropathy

“…Extracellular ATP may then activate the AMPK pathway to increase inflammation by upregulating metabolism [ 81 ]. While it is not intuitively obvious that increases in metabolism must correlate with an increase in inflammation, it is almost always the case, as basic increases of metabolism can strongly impact cellular activation [ 82 ].…”

Hyperthermia using nanoparticles – Promises and pitfalls

“…Owing to the prominence of fever in infectious or inflammatory environments, the immune consequences of fever have been studied extensively. Reduced IL-2 production from co-stimulation of CD4 + T cells via CD28 ligation has been reported during fever (72). Macrophages, the body’s scavengers of cellular debris, rapidly respond to various “alarm” signals generated from inflammatory sites by releasing pro-inflammatory mediators (73).…”