Initiating Immune Responses in States of Sterile Inflammation

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  2. Initiating Immune Responses in States of Sterile Inflammation

CITATION Diamond MS, Kinder M, Matsushita H, et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 2011; 208: 1989–2003.

CITATION Fuertes MB, Kacha AK, Kline J, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8a+ dendritic cells. J Exp Med 2011; 208: 2005–2016.

CITATION Hildner K, Edelson BT, Purtha WE, et al. Batf3 defi ciency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008; 322: 1097–1100.

CITATION Oberharnscheidt MH, Obhrai JS, Williams AL, et al. Type I interferons are not critical for skin allograft rejection or the generation of donor-specifi c CD8+ memory T cells. Am J Transplant 2009; 10: 162–167.

CITATION Robb RJ, Kreijveld E, Kuns RD, et al. Type I-IFNs control GVHD and GVL responses after transplantation. Blood 2011; 118: 3399–3409.


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  2. Initiating Immune Responses in States of Sterile Inflammation

The innate immune response is mediated through engagement of surface and intracellular receptors recognizing conserved molecular patterns of pathogens. Pattern recognition receptors (PRRs) on dendritic cells (DCs) transmit signals that activate antigen processing and presentation, up-regulate costimulatory molecules and cause migration from tissues to T-cell zones of lymphoid organs. These events bridge innate and adaptive immunity, leading to T-cell activation. PRRs are also invoked in response to tissue infl ammation, in which endogenous ligands are released and signal for removal of dying cells and tissue repair. It remains unclear how states of so-called sterile infl ammation evoke signals provoking the priming of T cells.

Two recent papers have used elegant approaches to uncovering steps in cutaneous tumors that initiate innate immune responses leading to tumor antigen-specific CD8 T-cell responses. One study, by Fuertes and colleagues, was prompted by observed correlations between expression levels of T-cell–specific and type I interferon (IFN)-induced transcripts in clinical melanomas, leading the authors to investigate the requirement for type I IFN signals in CD8 T-cell responses to tumor antigens in mice. Using the B16 melanoma model, these authors observed that induction of specific CD8 T cells required type I IFN-dependent cross-presentation of tumor antigens by DCs. A previous study by Hildner and colleagues had established that cross-priming relied on CD8a+ DCs, which require the transcription factor Batf3 during development. Reciprocal irradiation bone marrow chimeras of wild-type and type I IFN receptor signaling- and Batf3-deficient mice demonstrated that signaling through the type I IFN receptor on CD8a+ DCs was required for cross-priming of melanoma antigens, and that other DC subsets within the tumor microenvironment produced the type I IFN. Diamond and colleagues used a similar strategy of reciprocal bone marrow chimeras and a conditional deletion of type I IFN receptors in CD11c+ cells to demonstrate the critical role of type I IFN signaling to CD8a+ DCs in cross-priming of sarcoma antigens to induce specific CD8 T-cell responses.

Questions remain about initiation of the innate immune response that leads to priming of tumor antigen-specific CD8 T cells. What signals stimulate DCs to produce type I IFN, and what is the identity of the DC that produces IFN? How do the type I IFN-producing DCs and the CD8a+ DCs interact within the tumor microenvironment, and does type I IFN signaling provoke CD8a+ DC emigration from the tumor into the draining lymph node?

In transplantation, we should thus consider the role of recipient CD8a+ DCs and type I IFN signaling in cross-presentation of allograft antigens through the indirect pathway to generate CD8 T-cell responses. Robb et al. found that type I IFN receptor (R) signaling enhances CD8 cytotoxic T lymphocytes (CTLs) mediating graft-vs.-host disease in a mouse model. The rejection of complete MHC-mismatched or single minor antigen-mismatched skin grafts was not delayed in type I IFN R−/− recipients, but this rejection is mediated by donor-reactive T cells with direct as well as indirect alloantigen specificities, as determined by Oberharnscheidt and colleagues. Finally, adjunctive type I IFN therapy has been administered to hepatic allograft recipients with hepatitis C virus infection. The results revealed in the tumor models would suggest that such therapy could have unintended consequences in mobilizing the DCs to prime graft-reactive CD8 T-cell responses through cross-presentation of alloantigens.

Dr. Fairchild is with the Department of Immunology, Lerner Research Institute, at the Cleveland Clinic, Cleveland, Ohio