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PIRs mediate innate myeloid cell memory to nonself MHC molecules.

ABSTRACT: Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.

SUBMITTER: Dai H

PROVIDER: S-EPMC7379379 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Paired immunoglobulin-like receptors mediate innate memory to non-self MHC molecules

Project description:Abstract: Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. It is not known however whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously upon a second encounter. Here, we show that murine monocytes and macrophages acquire memory specific to MHC-I antigens and identify paired immunoglobulin-like receptors-A (PIR-A) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes. Data purpose: Targeting monocyte and macrophage receptors that detect MHC antigens blocks innate immune memory and attenuates transplant rejection

2020-06-05 | GSE147596 | GEO

Paired immunoglobulin-like receptors mediate innate memory to non-self MHC molecules

Project description:Paired immunoglobulin-like receptors mediate innate memory to non-self MHC molecules

| PRJNA615665 | ENA

MHC class II molecules enhance Toll-like receptor mediated innate immune responses.

Project description:BackgroundMajor histocompatibility complex (MHC) class II molecules play crucial roles in immune activation by presenting foreign peptides to antigen-specific T helper cells and thereby inducing adaptive immune responses. Although adaptive immunity is a highly effective defense system, it takes several days to become fully operational and needs to be triggered by danger-signals generated during the preceding innate immune response. Here we show that MHC class II molecules synergize with Toll-like receptor (TLR) 2 and TLR4 in inducing an innate immune response.Methodology/principal findingsWe found that co-expression of MHC class II molecules and TLR2 or TLR4 in human embryonic kidney (HEK) cells 293 leads to enhanced production of the anti-microbial peptide human-beta-defensin (hBD) 2 after treatment with TLR2 stimulus bacterial lipoprotein (BLP) or TLR4 ligand lipopolysaccharide (LPS), respectively. Furthermore, we found that peritoneal macrophages of MHC class II knock-out mice show a decreased responsiveness to TLR2 and TLR4 stimuli compared to macrophages of wild-type mice. Finally, we show that MHC class II molecules are physically and functionally associated with TLR2 in lipid raft domains of the cell membrane.Conclusions/significanceThese results demonstrate that MHC class II molecules are, in addition to their central role in adaptive immunity, also implicated in generating optimal innate immune responses.

| S-EPMC2808354 | biostudies-literature

Innate lymphoid cell memory.

Project description:Innate lymphoid cells (ILCs), including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells, comprise the first line of innate immune defense against pathogens and tumors. Over the past decade, accumulating evidence has demonstrated immunological memory in ILC subsets: for example, NK cells recall haptens, viruses, and cytokines; ILC1s recall haptens; and ILC2s recall cytokines. Although the development and functions of ILCs mirror those of T-cell subsets, ILC and T-cell memory exhibit both common characteristics and specific properties. Encouragingly, ILC memory has been found to confer benefits in long-term tumor control and vaccination, providing insight for novel memory ILC-based tumor immunotherapy and vaccine-development strategies. In this review, we discuss the evidence supporting ILC memory and present a comprehensive framework of the ILC memory system.

| S-EPMC6474199 | biostudies-literature

Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation.

Project description:MHC class II (MHCII)-influenced CD4(+) T cell differentiation and function play critical roles in regulating the development of autoimmunity. The lack of hematopoietic MHCII causes autoimmune disease that leads to severe wasting in syngeneic recipients. Using murine models of bone marrow transplantation (BMT), we find that MHCII(-/-)→wild-type BMT developed disease, with defective development of innate memory phenotype (IMP, CD44(hi)/CD62L(lo)) CD4(+) T cells. Whereas conventional regulatory T cells are unable to suppress pathogenesis, IMP CD4(+) T cells, which include conventional regulatory T cells, can suppress pathogenesis in MHCII(-/-)→wild-type chimeras. The functional development of IMP CD4(+) T cells requires hematopoietic but not thymic MHCII. B cells and hematopoietic CD80/86 regulate the population size, whereas MHCII expression by dendritic cells is sufficient for IMP CD4(+) T cell functional development and prevention of pathogenesis. Furthermore, the absence of Tec kinase IL-2-inducible T cell kinase in MHCII(-/-) donors leads to preferential development of IMP CD4(+) T cells and partially prevents pathogenesis. We conclude that dendritic cells-MHCII and IL-2-inducible T cell kinase regulate the functional development of IMP CD4(+) T cells, which suppresses the development of autoimmune disorder in syngeneic BMTs.

| S-EPMC4033297 | biostudies-literature

Generation of MHC class II-peptide ligands for CD4 T-cell allorecognition of MHC class II molecules.

Project description:The molecular and cellular mechanisms that underlie allorecognition of MHC class II molecules have been the subject of much debate and experimentation in recent decades. In this review, we discuss several aspects of MHC class II structure, peptide acquisition and TcR-MHC-peptide interactions that have particular relevance to recognition of cells bearing allogeneic class II molecules.First, MHC polymorphism is heavily biased toward those amino acids that influence stable peptide binding by MHC class II. Second, the peptide repertoire presented by class II molecules is highly diverse and can be edited substantially by the molecular catalyst HLA-DM and by tissue-specific expression of HLA-DO, stress and cytokines. Third, T-cell receptor docking onto MHC peptide consistently involves substantial contacts with the bound peptide in the MHC class II molecule. Finally, there is increasing evidence that T-cell recognition of MHC is, in part, germline encoded through T-cell-receptor V region contacts with MHC class II alpha helices.Together, these conclusions support the view that allorecognition of MHC class II molecules is likely to parallel key aspects of conventional CD4 T-cell recognition, with allele-dependent variation in peptide representation accounting in large part for the high precursor frequency of alloreactive CD4 T cells.

| S-EPMC3085167 | biostudies-literature

piRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline.

Project description:Organisms employ a fascinating array of strategies to silence invasive nucleic acids such as transposons and viruses. Although evidence exists for several pathways that detect foreign sequences, including pathways that sense copy number, unpaired DNA, or aberrant RNA (e.g., dsRNA), in many cases, the mechanisms used to distinguish "self" from "nonself" nucleic acids remain mysterious. Here, we describe an RNA-induced epigenetic silencing pathway that permanently silences single-copy transgenes. We show that the Piwi Argonaute PRG-1 and its genomically encoded piRNA cofactors initiate permanent silencing, and maintenance depends on chromatin factors and the WAGO Argonaute pathway. Our findings support a model in which PRG-1 scans for foreign sequences and two other Argonaute pathways serve as epigenetic memories of "self" and "nonself" RNAs. These findings suggest how organisms can utilize RNAi-related mechanisms to detect foreign sequences not by any molecular signature, but by comparing the foreign sequence to a memory of previous gene expression.

| S-EPMC3597741 | biostudies-literature

T-cell epitope prediction: rescaling can mask biological variation between MHC molecules.

Project description:Theoretical methods for predicting CD8+ T-cell epitopes are an important tool in vaccine design and for enhancing our understanding of the cellular immune system. The most popular methods currently available produce binding affinity predictions across a range of MHC molecules. In comparing results between these MHC molecules, it is common practice to apply a normalization procedure known as rescaling, to correct for possible discrepancies between the allelic predictors. Using two of the most popular prediction software packages, NetCTL and NetMHC, we tested the hypothesis that rescaling removes genuine biological variation from the predicted affinities when comparing predictions across a number of MHC molecules. We found that removing the condition of rescaling improved the prediction software's performance both qualitatively, in terms of ranking epitopes, and quantitatively, in the accuracy of their binding affinity predictions. We suggest that there is biologically significant variation among class 1 MHC molecules and find that retention of this variation leads to significantly more accurate epitope prediction.

| S-EPMC2650421 | biostudies-literature

Present Yourself! By MHC Class I and MHC Class II Molecules.

Project description:Since the discovery of MHC molecules, it has taken 40 years to arrive at a coherent picture of how MHC class I and MHC class II molecules really work. This is a story of the proteases and MHC-like chaperones that support the MHC class I and II molecules in presenting peptides to the immune system. We now understand that the MHC system shapes both the repertoire of presented peptides and the subsequent T cell response, with important implications ranging from transplant rejection to tumor immunotherapies. Here we present an illustrated review of the ins and outs of MHC class I and MHC class II antigen presentation.

| S-EPMC5159193 | biostudies-literature

Distinct mechanisms mediate naive and memory CD8 T-cell tolerance.

Project description:Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.

| S-EPMC3535649 | biostudies-literature

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