The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases

T Follicular helper (Tfh) cells, a unique subset of CD4+ T cells, play an essential role in B cell development and the formation of germinal centers (GCs). Tfh differentiation depends on various factors including cytokines, transcription factors and multiple costimulatory molecules. Given that OX40 signaling is critical for costimulating T cell activation and function, its roles in regulating Tfh cells have attracted widespread attention. Recent data have shown that OX40/OX40L signaling can not only promote Tfh cell differentiation and maintain cell survival, but also enhance the helper function of Tfh for B cells. Moreover, upregulated OX40 signaling is related to abnormal Tfh activity that causes autoimmune diseases. This review describes the roles of OX40/OX40L in Tfh biology, including the mechanisms by which OX40 signaling regulates Tfh cell differentiation and functions, and their close relationship with autoimmune diseases.

ontoFAST: An R package for interactive and semi-automatic annotation of characters with biological ontologies

The commonly used Entity-Quality (EQ) syntax provides rich semantics and high granularity for annotating phenotypes and characters using ontologies. However, EQ syntax might be time inefficient if this granularity is unnecessary for downstream analysis. We present an R package ontoFAST that aid production of fast annotations of characters and character matrices with biological ontologies. Its interactive interface allows quick and convenient tagging of character statements with necessary ontology terms. The annotations produced in ontoFAST can be exported in csv format for downstream analysis. Additinally, OntoFAST provides: (i) functions for constructing simple queries of characters against ontologies, and (ii) helper function for exporting and visualising complex ontological hierarchies and their relationships. OntoFAST enhances data interoperability between various applications and support further integration of ontological and phylogenetic methods. Ontology tools are underrepresented in R environment and we hope that ontoFAST will stimulate their further development.

A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.

Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

PD-L1/PD-1 blockade immunotherapy has significantly improved treatment outcome for several cancer types compared to conventional cytotoxic therapies. However, the specific molecular and cellular mechanisms behind its efficacy are currently unclear. There is increasing evidence in murine models and in patients that unveil the key importance of systemic immunity to achieve clinical responses under several types of immunotherapy. Indeed, PD-L1/PD-1 blockade induces the expansion of systemic CD8+ PD-1+ T cell subpopulations which might be responsible for direct anti-tumor responses. However, the role of CD4+ T cells in PD-L1/PD-1 blockade-induced anti-tumor responses has been less documented. In this review we focus on the experimental data supporting the “often suspected” indispensable helper function of CD4 T cells towards CD8 effector anti-tumor responses in cancer; and particularly, we highlight the recently published studies uncovering the key contribution of systemic CD4 T cells to clinical efficacy in PD-L1/PD-1 blockade therapies. We conclude and propose that the presence of specific CD4 T cell memory subsets in peripheral blood before the initiation of treatments is a strong predictor of responses in non-small cell lung cancer patients. Therefore, development of new approaches to improve CD4 responses before PD-L1/PD-1 blockade therapy could be the solution to increase response rates and survival of patients.

B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis

B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (TH) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor–primed TH cells. ICOS/ICOSL axis–mediated glucose incorporation and utilization were crucial for inflammatory TH subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory TH subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory TH cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory TH subsets.

SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

ABSTRACTConvalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can homeostatically proliferate, and can persist for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.

P039 Regional distribution of TCR Vδ1 and TCR Vδ2 cells in healthy and inflamed mucosa of inflammatory bowel disease

Background Vδ1+ and Vδ2+ are TCRγδ lymphocytes of the gut intraepithelial compartment that recognise proteins without help of antigen-presenting cells. Its relevance in inflammatory bowel disease (IBD) is unknown. Aim To measure Vδ1+ and Vδ2+ in T-cell subtypes [CD4+, CD8+, double positive (DP,CD4+CD8+), double negative (DN,CD4−CD8−) and CD103+] of healthy and IBD inflammed gut mucosa. Methods Twenty-six active IBD patients without immunosuppressants (n = 18 Crohn’s disease (CD), eight ulcerative colitis (UC)) and 10 healthy controls (paired biopsies of ileum, right and left colon) were included. Lymphocytes were analysed with LSRFortessa cytometer. Results expressed as % median (25–75%IQI). Results Healthy mucosa: reduction in ileum of total CD3+Vδ1+ due to CD3+CD8+Vδ1+ and CD3+DN_Vδ1+ Conclusion Reduction of Vδ1+ and Vδ2+, mainly of CD103+, may play a role in IBD pathophysiology by perpetuating inflammation. Increase of CD3+Vδ1+CD4+ in both Ileal CD and UC may compensate this decrease with a selective increase in ‘helper’ function.

Identification of Plant Compounds Involved in the Microbe-Plant Communication During the Coinoculation of Soybean with Bradyrhizobium elkanii and Delftia sp. strain JD2

Delftia sp. strain JD2 is a betaproteobacterium characterized as a plant growth–promoting bacterium with a ‘helper’ function, enhancing the performance of rhizobial inoculant strains during the coinoculation of alfalfa and clover. In this work we analyzed i) the effect of the coinoculation with Bradyrhizobium elkanii and Delftia sp. strain JD2 strains on the performance of soybean plants and ii) the production of a few secondary plant metabolites that would explain the positive effect of coinoculation on the growth and development of soybean plants. The results showed a beneficial effect of coinoculation on soybean growth, nodulation rate, and pulse yield, with the concomitant benefit for the agricultural economy. In addition, based on a metabolomics approach, we demonstrated that a different pattern of plant metabolites is being produced at different stages of plant growth. The new information suggests that the coinoculation of soybean changes the primary and secondary metabolism of the plant, including changes in the metabolic status of main and secondary nodules within the plant. The relevance of producing a different pattern of photosynthetic and photoprotective pigments, flavonoids, organic acids, and carbohydrates are discussed. Finally, we propose that JD2 could be used together with bradyrhizobia to manipulate the chemical composition of plant tissues, promoting the nutritional benefits and health of soybean.