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

Thermal and energetic constraints on ectotherm abundance: a global test using lizards

Abstract. Population densities of birds and mammals have been shown to decrease with body mass at approximately the same rate as metabolic rates increase, indicating that energetic needs constrain endotherm population densities. In ectotherms, the exponential increase of metabolic rate with body temperature suggests that environmental temperature may additionally constrain population densities. Here we test simple bioenergetic models for an ecologically important group of ectothermic vertebrates by examining 483 lizard populations. We find that lizard population densities decrease as a power law of body mass with a slope approximately inverse to the slope of the relationship between metabolic rates and body mass. Energy availability should limit population densities. As predicted, environmental productivity has a positive effect on lizard density, strengthening the relationship between lizard density and body mass. In contrast, the effect of environmental temperature is at most weak due to behavioral thermoregulation, thermal evolution, or the temperature dependence of ectotherm performance. Our results provide initial insights into how energy needs and availability differentially constrain ectotherm and endotherm density across broad spatial scales

Appendix A. Additional database methods.

Additional database methods

Appendix C. Results of maximum-likelihood models controlling for spatial and phylogenetic autocorrelation.

Results of maximum-likelihood models controlling for spatial and phylogenetic autocorrelation

Appendix D. Database literature sources.

Database literature sources

Appendix B. Additional methods for spatial and phylogenetic analysis.

Additional methods for spatial and phylogenetic analysis

IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches.

Immunoglobulin A (IgA) induction primarily occurs in intestinal Peyer's patches (PPs). However, the cellular interactions necessary for IgA class switching are poorly defined. Here we show that in mice, activated B cells use the chemokine receptor CCR6 to access the subepithelial dome (SED) of PPs. There, B cells undergo prolonged interactions with SED dendritic cells (DCs). PP IgA class switching requires innate lymphoid cells, which promote lymphotoxin-β receptor (LTβR)-dependent maintenance of DCs. PP DCs augment IgA production by integrin αvβ8-mediated activation of transforming growth factor-β (TGFβ). In mice where B cells cannot access the SED, IgA responses against oral antigen and gut commensals are impaired. These studies establish the PP SED as a niche supporting DC-B cell interactions needed for TGFβ activation and induction of mucosal IgA responses