ABSTRACT
Developing effective strategies to prevent or treat coronavirus disease 2019 (COVID-19) requires understanding the natural immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used an unbiased, genome-wide screening technology to determine the precise peptide sequences in SARS-CoV-2 that are recognized by the memory CD8+ T cells of COVID-19 patients. In total, we identified 3-8 epitopes for each of the 6 most prevalent human leukocyte antigen (HLA) types. These epitopes were broadly shared across patients and located in regions of the virus that are not subject to mutational variation. Notably, only 3 of the 29 shared epitopes were located in the spike protein, whereas most epitopes were located in ORF1ab or the nucleocapsid protein. We also found that CD8+ T cells generally do not cross-react with epitopes in the four seasonal coronaviruses that cause the common cold. Overall, these findings can inform development of next-generation vaccines that better recapitulate natural CD8+ T cell immunity to SARS-CoV-2.
Subject(s)
Betacoronavirus/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Betacoronavirus/isolation & purification , COVID-19 , Convalescence , Coronavirus/immunology , Coronavirus Infections/diagnosis , Coronavirus Nucleocapsid Proteins , Epitope Mapping , Epitopes, T-Lymphocyte , Female , Humans , Immunodominant Epitopes , Immunologic Memory , Male , Middle Aged , Nucleocapsid Proteins/immunology , Pandemics , Phosphoproteins , Pneumonia, Viral/diagnosis , Polyproteins , SARS-CoV-2 , Viral Proteins/immunology , Young AdultABSTRACT
B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory, signals for Tfh cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh cell development with those demonstrating that the latter requirement could be bypassed in lieu of that tendered by noncognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity.
Subject(s)
Antigens/immunology , B-Lymphocytes/immunology , Inducible T-Cell Co-Stimulator Ligand/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antigens, CD19/genetics , Antigens, CD19/immunology , Antigens, CD19/metabolism , B-Lymphocytes/metabolism , Cell Proliferation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Flow Cytometry , Inducible T-Cell Co-Stimulator Ligand/genetics , Inducible T-Cell Co-Stimulator Ligand/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Confocal , Nitrophenols/immunology , Ovalbumin/immunology , Phenylacetates/immunology , Proto-Oncogene Proteins c-bcl-6 , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes, Helper-Inducer/metabolismABSTRACT
Two studies in the current issue of Immunity (Pratama et al., 2013; Vogel et al., 2013) demonstrate that the RNA-binding proteins Roquin-1 and Roquin-2 have redundant function in the posttranscriptional repression of Icos messenger RNA by CD4(+) T cells.
ABSTRACT
MRL/MpJ-Fas(lpr/lpr)/J (MRL(lpr)) mice develop lupus-like disease manifestations in an IL-21-dependent manner. IL-21 is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets. Notably, autoreactive CD4(+) T and B cells spontaneously accumulate in MRL(lpr) mice and mediate disease pathogenesis. We sought to identify the particular lymphocyte effector subsets regulated by IL-21 in the context of systemic autoimmunity and, thus, generated MRL(lpr) mice deficient in IL-21R (MRL(lpr).IL-21R(-/-)). Lymphadenopathy and splenomegaly, which are characteristic traits of the MRL(lpr) model were significantly reduced in the absence of IL-21R, suggesting that immune activation was likewise decreased. Indeed, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R-deficient MRL(lpr) mice. Correspondingly, we observed a significant reduction in autoantibody titers. Activated CD4(+) CD44(+) CD62L(lo) T cells also failed to accumulate, and CD4(+) Th cell differentiation was impaired, as evidenced by a significant reduction in CD4(+) T cells that produced the pronephritogenic cytokine IFN-γ. T extrafollicular helper cells are a recently described subset of activated CD4(+) T cells that function as the primary inducers of autoantibody production in MRL(lpr) mice. Importantly, we demonstrated that T extrafollicular helper cells are dependent on IL-21R for their generation. Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL(lpr) mice.