Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection.

While the inhibitory receptor FcγRIIB has been shown to be upregulated on activated CD8+ T cells in both mice and humans, its effect on T cell fate during infection has not been fully elucidated. We identified an increase in FcγRIIB-expressing CD8+ T cells in patients with COVID-19 relative to healthy controls as well as in mouse models of viral infection. Despite its well-known role as an Fc receptor, FcγRIIB also ligates the immunosuppressive cytokine Fgl2, resulting in CD8+ T cell apoptosis.

Identification of indirect CD4 T cell epitopes associated with transplant rejection provides a target for donor-specific tolerance induction.

Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4 T cell epitopes-donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II-in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides.

From hero to zero: A single center retrospective review of the utility of routine physical crossmatching.

Pretransplantation human leukocyte antigen antibody testing is necessary to assess compatibility between donor and recipient pairs. Over the past decade, the virtual crossmatch (VXM) has replaced the physical crossmatch (PXM) as the main assessment of pretransplant histocompatibility. At our center, most transplants have proceeded based solely on the VXM, followed by a retrospective PXM.

Mitigating the Prozone-Like Effect in HLA Antibody Testing: A Case Report of Therapeutic Plasma Exchange for Antibody-Mediated Rejection Post-Heart Transplantation.

Therapeutic plasma exchange (TPE) is a cornerstone treatment for antibody-mediated rejection (AMR) post-organ transplantation, aiming to eliminate pathogenic donor-specific HLA antibodies (DSA). However, limitations in HLA antibody interpretation due to the prozone-like effect (PLE) can lead to inaccurate assessment of treatment efficacy. We present a case of a heart transplant recipient with suspected AMR, where an unexpected increase in DSA levels post-TPE prompted investigation into PLE.

Hiding in plain sight: Misinterpretation of immunogenic DPB epitopes within G/P groups.

The clinical impact of HLA DP antibodies is poorly understood, resulting in variable clinical strategies for transplant candidates and recipients with donor-directed HLA-DP antibodies. Complicating matters further, the DPB naming convention is not based on allelic homology and requires sequence alignments to identify potential immunogenic epitopes. Historically, G and P codes, which consolidated alleles that were identical over Exon 2, were used to simplify the reporting of HLA Class II typing as differences outside of Exon 2 have not been considered immunogenic (i.

The unnecessary use of short tandem repeat testing on bone marrow samples in patients after 1 year following allogeneic hematopoietic stem cell transplant.

Objectives: To determine whether the information provided by short tandem repeat (STR) testing and bone marrow (BM) biopsy specimens following hematopoietic stem cell transplant (HSCT) provides redundant information, leading to test overutilization, without additional clinical benefit.

Methods: Cases with synchronous STR and flow cytometric immunophenotyping (FCI) testing, as part of the BM evaluation, were assessed for STR/FCI concordance.

Results: Of 1199 cases (410 patients), we found the overall concordance between STR and FCI was 93%, with most cases (1063) classified as STR-/FCI-.

Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document.

Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification.

A Primer on Chimerism Analysis: A Straightforward, Thorough Review.

Short tandem repeat (STR) analysis to assess chimerism is a critical aspect of routine care particularly in patients facing stem cell transplants but is also relevant in other clinical scenarios. STR analysis provides a means to assess donor and recipient cellular origins in a patient, and, as such, can inform engraftment, rejection, and relapse status in stem cell transplant recipients. In this review of STR testing, the most commonly used method to assess chimerism, its background, procedural details, and clinical utility are discussed.

CMV Status Drives Distinct Trajectories of CD4+ T Cell Differentiation.

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual's immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to infections, vaccines, cancers, or rejection.

FcγRIIB is a T cell checkpoint in antitumor immunity.

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma.

Memory T cell-mediated rejection is mitigated by FcγRIIB expression on CD8 T cells.

Donor-reactive memory T cells generated via heterologous immunity represent a potent barrier to long-term graft survival following transplantation because of their increased precursor frequency, rapid effector function, altered trafficking patterns, and reduced reliance on costimulation signals for activation. Thus, the identification of pathways that control memory T cell survival and secondary recall potential may provide new opportunities for therapeutic intervention. Here, we discovered that donor-specific effector/memory CD8 T cell populations generated via exposure to acute vs latent vs chronic infections contain differential frequencies of CD8 T cells expressing the inhibitory Fc receptor FcγRIIB.

CD45RB Status of CD8 T Cell Memory Defines T Cell Receptor Affinity and Persistence.

The identity of CD45 isoforms on the T cell surface changes following the activation of naive T cells and impacts intracellular signaling. In this study, we find that the anti-viral memory CD8 T pool is unexpectedly comprised of both CD45RB and CD45RB populations. Relative to CD45RB memory T cells, CD45RB memory T cells have lower affinity and display greater clonal diversity, as well as a persistent CD27 phenotype.

Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8 T Cell Apoptosis to Limit T Cell Immunity.

Effector CD8 T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8 T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8 T cell-intrinsic genetic deletion of Fcgr2b increased CD8 effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models.

When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity.

Purpose Of Review: Studies on adaptive cells have largely focused on features that are specific to adaptive immunity. However, adaptive cells utilize innate cell features to modulate their responses, and this area of T and B-cell biology is understudied. This review will highlight recent work done to understand how innate features of adaptive immune cells modulate alloimmunity.

Out with the old, in with the new: Virtual versus physical crossmatching in the modern era.

The virtual crossmatch (VXM) is gaining acceptance as an alternative approach to assess donor:recipient compatibility prior to transplantation. In contrast to a physical crossmatch, the virtual crossmatch does not require viable donor cells but rather relies on complete HLA typing of the donor and current antibody assessment of the recipient. Thus, the VXM can be performed in minutes which allows for faster transplant decisions thereby increasing the likelihood that organs can be shipped across significant distances yet safely transplanted.

Influence of T Cell Coinhibitory Molecules on CD8 Recall Responses.

T cell co-signaling molecules play an important role in fine-tuning the strength of T cell activation during many types of immune responses, including infection, cancer, transplant rejection, and autoimmunity. Over the last few decades, intense research into these cosignaling molecules has provided rich evidence to suggest that cosignaling molecules may be harnessed for the treatment of immune-related diseases. In particular, coinhibitory molecules such as programmed-death 1, 2B4, BTLA, TIGIT, LAG-3, TIM-3, and CTLA-4 inhibit T cell responses by counteracting TCR and costimulatory signals, leading to the inhibition of proliferation and effector function and the downregulation of activation and adhesion molecules at the cell surface.

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists.

Adoptive therapy with ex vivo-expanded genetically modified antigen-specific T cells can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. Lower rates of ex vivo expansion and clinical response using anti-CD19 chimeric antigen receptor (CAR) T cells have been seen in heavily pretreated lymphoma patients compared with B-cell acute lymphoblastic leukemia patients and motivate the development of novel strategies to enhance ex vivo T cell expansion and their persistence in vivo.

Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection.

SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4-Cre SHP1(fl/fl) conditional knockout thymocytes using CD53, TCRβ, CD69, CD4, and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53(+) ), single-positive thymocytes. Using Ca(2+) flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, postselection thymocytes.