We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFN-γ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B in active germinal centers) and cytotoxic (GZMB+CD8+ and GZMB+CD68+ TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a CD25+CXCR5+GARP+FOXP3+ phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-β-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and CD8+ TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.

/pdf/functional-th1-oriented-t-follicular-helper-cells-that-2wi35n2hrp.pdf

Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity

Background: COVID-19 has become a pandemic since December 2019, causing millions of deaths worldwide. It has a wide spectrum of severity, ranging from mild infection to severe illness requiring mechanical ventilation. In the middle of a pandemic, when medical resources (including mechanical ventilators) are scarce, there should be a scoring system to provide the clinicians with the information needed for clinical decision-making and resource allocation. Objectives: This study aimed to develop a scoring system based on the data obtained on admission, to predict the need for mechanical ventilation in COVID-19 patients. Methods: This study included COVID-19 patients admitted to Sina Hospital, Tehran University of Medical Sciences from February 20 to May 29, 2020. Patients’ data on admission were retrospectively recruited from Sina Hospital COVID-19 Registry (SHCo-19R). Mul-tivariable logistic regression and receiver operating characteristic (ROC) curve analysis were performed to identify the predictive factors for mechanical ventilation. Results: A total of 681 patients were included in the study;74 patients (10.9%) needed mechanical ventilation during hospitalization, while 607 (89.1%) did not. Multivariate logistic analysis revealed that age (OR,1.049;95% CI:1.008-1.091), history of diabetes mellitus (OR,3.216;95% CI:1.134-9.120), respiratory rate (OR,1.051;95% CI:1.005-1.100), oxygen saturation (OR,0.928;95% CI:0.872-0.989), CRP (OR,1.013;95% CI:1.001-1.024) and bicarbonate level (OR,0.886;95% CI:0.790-0.995) were risk factors for mechanical ventilation during hospitalization. Conclusions: A risk score has been developed based on the available data within the first hours of hospital admission to predict the need for mechanical ventilation. This risk score should be further validated to determine its applicability in other populations. © 2021, Author(s).

Predicting risk score for mechanical ventilation in hospitalized adult patients suffering from covid-19

Abstract Background Immunization of vulnerable populations with distinct immunity often results in suboptimal immunogenicity, durability, and efficacy. Methods Safety and immunogenicity profiles of BNT162b2 messenger RNA coronavirus disease 2019 (COVID-19) vaccine, among people living with human immunodeficiency virus (HIV), were evaluated in 28 perinatally HIV-infected patients under antiretroviral therapy (ART) and 65 healthy controls (HCs) with no previous history of COVID-19. Thus, we measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific humoral and CD4+ T cell responses. Samples were collected before vaccination (baseline, day [D] 0), at the second dose (D21), and at 4 weeks (D28) and 6 months (D180) after D0. Proteomic profiles at D0 and D28 were assessed with a multiplexed proximity extension assay (Olink) on plasma samples. Results All HIV-infected patients mounted similar anti–SARS-CoV-2 humoral responses to those of HCs, albeit with lower titers of anti-trimeric S at D28 (P = .01). Only peripheral blood mononuclear cells of HIV-infected patients demonstrated at D28 an impaired ability to expand their specific (CD40L+) CD4+ T-cell populations. Similar humoral titers were maintained between the 2 groups at 6-months follow-up. We additionally correlated baseline protein levels to either humoral or cellular responses, identifying clusters of molecules involved in immune response regulation with inverse profiles between the 2 study groups. Conclusions Responses of ART-treated HIV-infected patients, compared to those of HCs, were characterized by distinct features especially within the proteomic compartment, supporting their eligibility to an additional dose, similarly to the HC schedule.

/pdf/perinatally-human-immunodeficiency-virus-infected-2hrdquob.pdf

Perinatally Human Immunodeficiency Virus–Infected Adolescents and Young Adults Demonstrate Distinct BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine Immunogenicity

Hepatitis B has become one of the major global health threats, especially in developing countries and regions. Hepatitis B virus infection greatly increases the risk for liver diseases such as cirrhosis and cancer. However, treatment for hepatitis B is limited when considering the huge base of infected people. The immune response against hepatitis B is mediated mainly by CD8+ T cells, which are key to fighting invading viruses, while regulatory T cells prevent overreaction of the immune response process. Additionally, follicular T helper cells play a key role in B-cell activation, proliferation, differentiation, and formation of germinal centers. The pathogenic process of hepatitis B virus is generally the result of a disorder or dysfunction of the immune system. Therefore, we present in this review the critical functions and related biological processes of regulatory T cells and follicular T helper cells during HBV infection.

/pdf/the-role-of-regulatory-t-cells-and-follicular-t-helper-cells-1qzmrhfj.pdf

The role of regulatory T cells and follicular T helper cells in HBV infection

Abstract Purpose Humoral and cellular immune responses were described after COVID-19 vaccination in patients with common variable immunodeficiency disorder (CVID). This study aimed to investigate SARS-CoV-2-specific antibody quality and memory function of B cell immunity as well as T cell responses after COVID-19 vaccination in seroresponding and non-responding CVID patients. Methods We evaluated antibody avidity and applied a memory B cell ELSPOT assay for functional B cell recall memory response to SARS-CoV-2 after COVID-19 vaccination in CVID seroresponders. We comparatively analyzed SARS-CoV-2 spike reactive polyfunctional T cell response and reactive peripheral follicular T helper cells (pT FH ) by flow cytometry in seroresponding and non-seroresponding CVID patients. All CVID patients had previously failed to mount a humoral response to pneumococcal conjugate vaccine. Results SARS-CoV-2 spike antibody avidity of seroresponding CVID patients was significantly lower than in healthy controls. Only 30% of seroresponding CVID patients showed a minimal memory B cell recall response in ELISPOT assay. One hundred percent of CVID seroresponders and 83% of non-seroresponders had a detectable polyfunctional T cell response. Induction of antigen-specific CD4 + CD154 + CD137 + CXCR5 + pT FH cells by the COVID-19 vaccine was higher in CVID seroresponder than in non-seroresponder. Levels of pT FH did not correlate with antibody response or avidity. Conclusion Reduced avidity and significantly impaired recall memory formation after COVID-19 vaccination in seroresponding CVID patients stress the importance of a more differentiated analysis of humoral immune response in CVID patients. Our observations challenge the clinical implications that follow the binary categorization into seroresponder and non-seroresponder. 

https://link.springer.com/content/pdf/10.1007/s10875-023-01468-w.pdf

Impaired B Cell Recall Memory and Reduced Antibody Avidity but Robust T Cell Response in CVID Patients After COVID-19 Vaccination

T follicular helper (TFH) cells, a critical subset of CD4+ T cells, provide help to B cells during the procession of the humoral immune response in the germinal center (GC) and extrafollicular sites. CXCR5+ CD4+ T cells in human circulating blood, referred to herein as peripheral TFH (pTFH) cells, share phenotypes and functional properties with TFH cells in GC. Hepatitis B vaccine protects about 60% of the chronic hepatitis C patients from hepatitis B. The immunological bases that lead to the induction of protective antibody response is not well understood. In the present study, the pTFH cells subsets were determined in 18 healthy controls (anti-HBs ≥ 100 mIU/mL; HC), 21 nonresponders (anti-HBs < 10 mIU/mL; NR), and 23 weak responders (10 mIU/mL ≤ anti-HBs < 100 mIU/mL; WR) of chronic hepatitis patients upon routine hepatitis B vaccination. Though the frequency of the pTFH cell was equivalent in HC, WR, and NR, ICOS+ pTFH cells in HC underwent expansion with increased IL-21 secretion and production of serum anti-HBs response at 4 weeks after a full course of hepatitis B vaccination. These changes were not shown in both NR and WR. Analysis of ICOS+ pTFH cells represents a novel cellular determinant of the hepatitis B vaccine-induced humoral immune response, which may have relevance for design of hepatitis B vaccine.

Induction of peripheral blood T follicular helper cells expressing ICOS correlates with antibody response to hepatitis B vaccination

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Induction of peripheral blood T follicular helper cells expressing ICOS correlates with antibody response to hepatitis B vaccination