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

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.This work was supported in part by a grant from the Australian National Health and Medical Research Council (APP1105312) to S.R. McColl, J.G. Cyster, and I. Comerford, J.G. Cyster is an investigator of the Howard Hughes Medical Institute. E.E. Kara is supported by an Australian postgraduate award, a Norman and Patricia Polglase scholarship, and a National Health and Medical Research Council C.J. Martin Overseas Biomedical fellowship

IL-17-producing γδ T cells switch migratory patterns between resting and activated states

Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδ T17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesionsThis work was supported by National Health and Medical Research Council project grants 1066781 and 1054925. A.K. is supported by the Sylvia and Charles Viertel foundation

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses

The CC-chemokine receptor 6 (CCR6) can be detected on naïve and activated B cells. Counterintuitively, its absence accelerates the appearance of germinal centres (GC) and increases the production of low-affinity antibodies. The detailed mechanism of CCR6 function during the humoral response has remained elusive but previously we identified a distinct CCR6(high) B cell population in vivo early after antigenic challenge. In this study, we defined this population specifically as early, activated pre-GC B cells. In accordance, we show that CCR6 is up-regulated rapidly within hours on protein or mRNA level after activation in vitro. Additionally, only activated B cells migrated specifically towards CCL20, the specific ligand for CCR6. Lack of CCR6 increased the dark zone/light zone ratio of GC and led to decreased antigen-specific IgG1 and IgG2a antibody generation in a B cell intrinsic manner in mixed bone marrow chimeras. In contrast, antigen-specific IgM responses were normal. Hence, CCR6 negatively regulates entry of activated, antigen-specific pre-GC B cells into the GC reaction.Dorothea Reimer, Adrian YS Lee, Jennifer Bannan, Phillip Fromm, Ervin E Kara, Iain Comerford, Shaun McColl, Florian Wiede, Dirk Mielenz and Heinrich Körne

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

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