X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors and is expressed in specific lymphoid lineages. In T cells, SAP relays activatory signals from the T-cell receptor but in its absence SH2 containing protein tyrosine phosphase-1 (SHP1), SH2 containing protein tyrosine phosphase-2 (SHP2), and SH2 containing inositol 5'-phosphatase proteins (SHIP) induce T-cell inhibitory signals leading to abnormal T-cell responses. This results in severe clinical manifestations including immune dysregulation, dysgammaglobulinemia, lymphoma, and hemophagocytic lymphohistiocytosis. Current treatment relies on supportive therapies including immunoglobulin replacement and symptom-directed therapy, with hematopoietic stem cell transplant offering the only curative option.
As most XLP symptoms are due to defective T-cell function, this study investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP.
Healthy donor and XLP patient T cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24 hours) and functional assays were performed to assess follicular TH (TFH) cell function, CD8 cytotoxicity, and sensitivity to restimulation-induced cell death. Additionally, SAP-deficient (SAPy/-) mice were treated with RMC-4550 before T-cell mediated challenge with 4-hydroxy-3-nitrophenylacetly conjugated chicken gammaglobulin and subsequent assessment of humoral immunity analyzing TFH cell population, germinal center formation, and antigen-dependent immunoglobulin secretion.
This study shows that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAPy/- model, demonstrating restoration of TFH cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and restimulation-induced cell death.
These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for patients with XLP.
Copyright © 2022. Published by Elsevier Inc.

(1) Background: Vascular surgery operations are hampered by high failure rates and frequent occurrence of peri-operative cardiovascular complications. In pre-clinical studies, pre-operative restriction of proteins and/or calories (PCR) has been shown to limit ischemia-reperfusion damage, slow intimal hyperplasia, and improve metabolic fitness. However, whether these dietary regimens are feasible and safe in the vascular surgery patient population remains unknown. (2) Methods: We performed a randomized controlled trial in patients scheduled for any elective open vascular procedure. Participants were randomized in a 3:2 ratio to either four days of outpatient pre-operative PCR (30% calorie, 70% protein restriction) or their regular ad-libitum diet. Blood was drawn at baseline, pre-operative, and post-operative day 1 timepoints. A leukocyte subset flow cytometry panel was performed at these timepoints. Subcutaneous/perivascular adipose tissue was sampled and analyzed. Follow-up was one year post-op. (3) Results: 19 patients were enrolled, of whom 11 completed the study. No diet-related reasons for non-completion were reported, and there was no intervention group crossover. The PCR diet induced weight loss and BMI decrease without malnutrition. Insulin sensitivity was improved after four days of PCR (p = 0.05). Between diet groups, there were similar rates of re-intervention, wound infection, and cardiovascular complications. Leukocyte populations were maintained after four days of PCR. (4) Conclusions: Pre-operative PCR is safe and feasible in elective vascular surgery patients.

Resident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment.
RNA and protein expressions of chemokine receptors in CD8+ resident memory T cells in human ovarian tumor-infiltrating CD8+ T cells and their association with survival were analyzed. The role of CXCR6 on antitumor T cells was investigated using prophylactic vaccine models in murine ovarian cancer.
Chemokine receptor profiling of CD8+CD103+ resident memory tumor-infiltrating lymphocytes in patients with ovarian cancer revealed high expression of CXCR6. Analysis of The Cancer Genome Atlas (TCGA) (ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory, tumor-specific memory CD8+ T cells. CXCR6-deficient tumor-specific CD8+ T cells showed reduced retention in tumor tissues, leading to diminished resident memory responses and poor control of ovarian cancer.
CXCR6, by promoting retention in tumor tissues, serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory responses in cancers.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

HSV-2 infection-induced CXCR3 ligands are important for the recruitment of virus-specific CD8+ T cells, but their impact on CD4+ T cell trafficking remains to be further determined. Given that recruitment of CD4+ T cells to infection areas may be one of the mechanisms that account for HSV-2 infection-mediated enhancement of HIV-1 sexual transmission, here we investigated the functionality of HSV-2 infection-induced CXCR3 ligands CXCL9, CXCL10, and CXCL11 in vivo and in vitro, and determined the viral components responsive for such induction and the underlying mechanisms. We first found that the expression of CXCR3 ligands CXCL9, CXCL10, and CXCL11 was increased in mice following vaginal challenge with HSV-2, while CXCL9 played a predominant role in the recruitment of CD4+ T cells to the vaginal foci of infected mice. HSV-2 infection also induced the production of CXCL9, CXCL10, and CXCL11 in human cervical epithelial cells. Of note, although HSV-2 induced the expression of all the three CXCR3 ligands, the induced CXCL9 appeared to play a predominant role in promoting CD4+ T cell migration, reflecting that the concentrations of CXCL10 and CXCL11 required for CD4+ T cell migration are higher than that of CXCL9. We further revealed that, ICP4, an immediate-early protein of HSV-2, is crucial in promoting CXCR3 ligand expression through the activation of p38 MAPK pathway. Mechanistically, ICP4 binds to corresponding promoters of CXCR3 ligands via interacting with the TATA binding protein (TBP), resulting in the transcriptional activation of the corresponding promoters. Taken together, our study highlights HSV-2 ICP4 as a vital viral protein in promoting CXCR3 ligand expression and CXCL9 as the key induced chemokine in mediating CD4+ T cell migration. Findings in this study have shed light on HSV-2 induced leukocyte recruitment which may be important for understanding HSV-2 infection-enhanced HIV-1 sexual transmission and the development of intervention strategies.