TIGITTfh show poor B-helper function and negatively correlate with SARS-CoV-2 antibody titre.

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation.

IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation.

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone.

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg.

Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity.

Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous.

Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.

Follicular helper T (T) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether T cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS) T cells and other ICOS populations, including peripheral helper T cells, were highly sensitive to costimulation blockade.

CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells.

CTLA-4 is a critical negative regulator of the immune system and a major target for immunotherapy. However, precisely how it functions in vivo to maintain immune homeostasis is not clear. As a highly endocytic molecule, CTLA-4 can capture costimulatory ligands from opposing cells by a process of transendocytosis (TE).

T Cell/B Cell Collaboration and Autoimmunity: An Intimate Relationship.

Co-ordinated interaction between distinct cell types is a hallmark of successful immune function. A striking example of this is the carefully orchestrated cooperation between helper T cells and B cells that occurs during the initiation and fine-tuning of T-cell dependent antibody responses. While these processes have evolved to permit rapid immune defense against infection, it is becoming increasingly clear that such interactions can also underpin the development of autoimmunity.