Type I IFN Substitutes for T Cell Help during Viral Infections

Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8+ T cell responses. In this study, we report that in the context of a CD8+ T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8+ T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter–glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-β receptor (LTβR) in DC are also required for the proliferation of autoreactive CD8+ T cells, the upregulation of VLA4/LFA1 on activated CD8+ T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8+ T cell proliferation, accumulation of CD8+ T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTβR−/− DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/IFN-I axis is essential for programming of CD8+ T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTβR axis will provide valuable therapeutic insights for treatment of CD8+ T cell–mediated autoimmune diseases.

Section: Discussionmentioning

confidence: 84%

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Maître

Cummings

et al. 2015

“…In these settings, the lack of CD4 T cell help during priming results in defective memory CTLs that mediate effector functions but do not undergo a second round of clonal expansion on Ag rechallenge (7,11,12). However, several studies in mice have indicated that the requirement for CD4 T cell help is not absolute and can be bypassed by the intense inflammatory environment elicited by certain pathogens (13)(14)(15)(16)(17)(18) or several TLR ligands (13,(19)(20)(21).…”

mentioning

confidence: 99%

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

Hervás-Stubbs

Mancheño

Riezu-Boj

et al. 2012

Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α–primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15−/− and IL-7−/− recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2+ CD8 T cells with autologous dendritic cells loaded with MART126–35 peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

“…IFNs-I also promote CTL responses in an indirect manner by delivering maturation signals to DCs and by modulating the degree of Ag presentation and costimulation (5). Furthermore, T cell-intrinsic IFN-I signaling was reported to substitute for T cell help to CTLs (6). Although not considered specifically to be signal 3 cytokines, other cytokines, such as the common cytokine receptor g-chain family (7) and IFN-g (8), also have a profound effect on the CTL response.…”

mentioning

confidence: 99%

Conventional but Not Plasmacytoid Dendritic Cells Foster the Systemic Virus–Induced Type I IFN Response Needed for Efficient CD8 T Cell Priming

Hervás-Stubbs

Riezu-Boj

Mancheño

et al. 2014

Plasmacytoid dendritic cells (pDCs) are considered to be the principal type-I IFN (IFN-I) source in response to viruses, whereas the contribution of conventional DCs (cDCs) has been underestimated because, on a per-cell basis, they are not considered professional IFN-I–producing cells. We have investigated their respective roles in the IFN-I response required for CTL activation. Using a nonreplicative virus, baculovirus, we show that despite the high IFN-I–producing abilities of pDCs, in vivo cDCs but not pDCs are the pivotal IFN-I producers upon viral injection, as demonstrated by selective pDC or cDC depletion. The pathway involved in the virus-triggered IFN-I response is dependent on TLR9/MyD88 in pDCs and on stimulator of IFN genes (STING) in cDCs. Importantly, STING is the key molecule for the systemic baculovirus-induced IFN-I response required for CTL priming. The supremacy of cDCs over pDCs in fostering the IFN-I response required for CTL activation was also verified in the lymphocytic choriomeningitis virus model, in which IFN-β promoter stimulator 1 plays the role of STING. However, when the TLR-independent virus-triggered IFN-I production is impaired, the pDC-induced IFNs-I have a primary impact on CTL activation, as shown by the detrimental effect of pDC depletion and IFN-I signaling blockade on the residual lymphocytic choriomeningitis virus–triggered CTL response detected in IFN-β promoter stimulator 1−/− mice. Our findings reveal that cDCs play a major role in the TLR-independent virus-triggered IFN-I production required for CTL priming, whereas pDC-induced IFNs-I are dispensable but become relevant when the TLR-independent IFN-I response is impaired.