The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100-1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.
Efforts are being made worldwide to understand the immune response to SARS-CoV-2, the virus responsible for the COVID-19 pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7
+
COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response.
In vitro
peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity towards circulating OC43 and HKU-1 beta coronaviruses, but not 229E or NL63 alpha coronaviruses, due to different peptide conformations. TCR sequencing indicated cross-reactivity was driven by private T cell receptor repertoires with a bias for TRBV27 and a long CDR3β loop. Together, our findings demonstrate the basis of selective T cell cross-reactivity towards an immunodominant SARS-CoV-2 epitope and its homologues from seasonal coronaviruses, suggesting long-lived protective immunity.
Malaria is a highly prevalent disease caused by infection by Plasmodium spp., which infect hepatocytes and erythrocytes. Blood-stage infections cause devastating symptoms and can persist for years. Antibodies and CD4(+) T cells are thought to protect against blood-stage infections. However, there has been considerable difficulty in developing an efficacious malaria vaccine, highlighting our incomplete understanding of immunity against this disease. Here, we used an experimental rodent malaria model to show that PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells. Furthermore, in contrast to widely held views, parasite-specific CD8(+) T cells are required to control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4(+) T cells are present. Our findings provide a molecular explanation for chronic malaria that will be relevant to future malaria-vaccine design and may need consideration when vaccine development for other infections is problematic.
Key Points
Donor-derived Tc17 cells differentiate early after allogeneic transplant in response to IL-6 and alloantigen presentation by host DCs. Tc17 are highly proinflammatory and pathogenic posttransplant, but exert limited or no GVL activity.
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