Type I IFN-Dependent T Cell Activation Is Mediated by IFN-Dependent Dendritic Cell OX40 Ligand Expression and Is Independent of T Cell IFNR Expression

Abstract

Type-I-interferons are important for direct control of viral infection and for generation of adaptive immune responses. Recently, direct stimulation of CD4+ T cells via type-I-interferon receptor has been shown to be necessary for the formation of function CD4+ T cell responses. In contrast, we find that CD4+ T cells do not require intrinsic type-I-interferon signals in response to combined TLR/anti-CD40 vaccination. Rather, the CD4 response is dependent on the expression of type-I-interferon receptor (IFNαR) on innate cells. Further, we find that DC expression of the TNF ligand, OX40L, was dependent on type I IFN signaling in the DC, resulting in a reduced CD4+ T cell response that could be substantially rescued by an agonistic antibody to the receptor, OX40. Taken together, we show that the IFNαR dependence of the CD4+ T cell response is accounted for exclusively by defects in DC activation.

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…(combined TLR/CD40 vaccination) (23,24). In contrast to other forms of vaccination/immunization, T-cell intrinsic stimulation from classical Signal 3 cytokines such as type I IFN or IL-12 were not required for T-cell expansion, polarization, or memory generation (25,26). Literature searches for other cytokines capable of dramatically influencing T-cell polarization/differentiation drew attention to the IL-12 family member IL-27 (11,27,28).…”

“…This failure to recapitulate the magnitude of the T-cell response to Poly I:C/αCD40 indicates that IL-27 cannot completely replicate the complex inflammatory environment instigated by the TLR agonist. We and others previously published on an important role for CD70-CD27 interactions in the T-cell response to combined TLR/ CD40 immunization (24,25,54) as well as to infectious challenge/ vaccination (55)(56)(57)(58). Because IL-27 and CD27 separately are required for maximal T-cell responses after subunit vaccination, neither alone is therefore sufficient for maximal T-cell expansion.…”

OX40, OX40L and Autoimmunity: a Comprehensive Review

“…Factors promoting OX40L expression other than antigen presentation and accompanying co-stimulation include interferon gamma (IFNγ), in an IFNγ-receptor-dependent mechanism [43,44], prostaglandin E2 [45], TSLP [46] and IL-18 [47]. Finally, human serum soluble OX40L increases with age [48].…”

Red blood cell alloimmunization is influenced by the delay between Toll-like receptor agonist injection and transfusion

“…Specifically, the injection of TLR3 agonists combined with CD40 stimulation facilitates the secretion of pro-inflammatory cytokines by CD4 + T cells by promoting the expression of CD134. 40,50 Cross-linking between CD134 on CD4 + T cells and CD252 on activated B cells results in B-cell proliferation and the secretion of all Ig isotypes. 51 This high level of expression of CD134 at 7 days and its involvement in B-cell antibody secretion suggest a direct link between the CD4 + T-cell response and the level of antibody production, which were concordant for the same time interval between agonist injection and transfusion.…”

“…DC were fixed and permeabilized with a commercial kit (eBioscience) for intramembranous staining with CD283-PE (Biolegend, San Diego, CA, USA), IL12-FITC and IFNγ-AF700 (BD Biosciences). The HEL protein contains an immunodominant peptide, NR16 (HEL [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] : NTDGSTDYGILQIN-SR). NR16-presenting DC were studied using an AW3.18 antibody.…”