Atypical chemokine receptor 4 shapes activated B cell fate

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate

CXCR5⁺ follicular cytotoxic T cells control viral infection in B cell follicles

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell–derived malignancies

CXCR5+CD8+ T Cells Shape Antibody Responses In Vivo Following Protein Immunisation and Peripheral Viral Infection

Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4+T cells in this process have been well-characterised. In contrast, regulation of antibody responses by CD8+T cells is significantly less defined. CD8+T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8+T cells that co-opt a differentiation program characteristic of CD4+T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5+CD8+T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5+CD8+T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responsesin vivoin these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5+CD8+T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I orCxcr5-/-OT-I cells revealed that CXCR5+CD8+T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8+T cells to antibody responses, expanding the functionality of the adaptive immune system.</jats:p

Novel T_H subsets in inflammation.

<p>(<b>A</b>) T_H17 and T_H22 cells have overlapping functions in the mouse. Via production of the inflammatory mediators IL-17A, IL-17F, GMCSF (T_H17), and IL-22 (T_H22), these T_H subsets mediate protective immunity against extracellular pathogens intimately associated with mucosal barriers. (<b>B</b>) T_H9-cell-derived IL-9 may play an important role in antiparasitic immunity via mediating mast cell activation and mastocytosis, increasing the chemotactic potential of an inflammatory site via regulation of inflammatory chemokine production, and promote basophil and eosinophil function.</p

Currently known T_H cell subsets.

<p>Polarising cytokines encountered during T_H cell differentiation drive the expression of subset-specific transcription factors, which imprint subset-specific transcriptomes in the T_H cell. These transcription factors define the effector function and migratory capability of the T_H cell via regulation of subset-specific cytokines and chemokine receptors.</p

Mechanism of action of T_FH cells.

<p>T_FH cells are effector T_H cells that govern the quality and magnitude of an antibody response via regulation of B cell selection, differentiation, proliferation, and class switch recombination. T_FH cells execute these effector functions via expression of various cell surface proteins and cytokines (including IL-21). They are generated during antigen presentation in the T cell areas of secondary lymphoid organs in the presence of IL-21 and IL-6, which is thought to upregulate their master transcription factor Bcl6 (pre-T_FH), after which they migrate to the T∶B border where interaction with cognate B cells regulates a number of processes including promoting survival of recently activated B cells, regulating the fate decision of a B cell down extrafollicular plasmablast or germinal center (GC) B cell differentiation pathways, and induction of class switch recombination in GC B cells. Stable interactions with cognate B cells at this border also consolidate the T_FH cell programme (pre-T_FH to T_FH cell differentiation) with further upregulation of Bcl6 and entry into developing GCs. Within GCs, T_FH cells are crucial for the regulation of affinity maturation, development of memory B cell populations, and high-affinity antibody responses via regulation of long-lived plasma cell differentiation.</p

The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Perhexiline, a prophylactic anti-anginal drug, has been reported to have anti-tumour effects both in vitro and in vivo. Perhexiline as used clinically is a 50:50 racemic mixture ((R)-P) of (−) and (+) enantiomers. It is not known if the enantiomers differ in terms of their effects on cancer. In this study, we examined the cytotoxic capacity of perhexiline and its enantiomers ((−)-P and (+)-P) on CRC cell lines, grown as monolayers or spheroids, and patient-derived organoids. Treatment of CRC cell lines with (R)-P, (−)-P or (+)-P reduced cell viability, with IC50 values of ~4 µM. Treatment was associated with an increase in annexin V staining and caspase 3/7 activation, indicating apoptosis induction. Caspase 3/7 activation and loss of structural integrity were also observed in CRC cell lines grown as spheroids. Drug treatment at clinically relevant concentrations significantly reduced the viability of patient-derived CRC organoids. Given these in vitro findings, perhexiline, as a racemic mixture or its enantiomers, warrants further investigation as a repurposed drug for use in the management of CRC.</jats:p