Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.This work was funded by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (to E.K. Deenick, C.S. Ma, D.A. Fulcher, M.C. Cook, and S.G. Tangye) and the Rockefeller University Center for 541 Clinical and Translational science (5UL1RR024143 to J.L. Casanova). C.S. Ma is a recipient of a Career Development Fellowship, L.J. Berglund is a recipient of a Medical Postgraduate Scholarship, and S.G. Tangye is a recipient of a Principal Research Fellowship from the NHMRC of Australia. L. Moens is the recipient of a Postdoctoral Fellowship from the Research Foundation-Flanders (FWO), Belgium

Racialized Architectural Space: A Critical Understanding of its Production, Perception and Evaluation

Academic inquiry into the concept of space as racialized can be traced back to at least as far as the turn of the twentieth century with sociologist W. E. B. Dubois’ promulgation of the “color-line” theory. More recently, numerous postmodern scholars from a variety of fields have elucidated the various ways in which physical space (i.e., the built environment), as a social product, embodies racialized ideologies exhibited and reproduced by segregation, economics and other social practices. The dialogue on race and space has primarily been limited to the urban scales of city, neighborhood, community and street. Socio-spatial research that centers around race rarely addresses this phenomenon at the scale of architecture – the individual building or a particular development. Such a failure to critically examine the role of the architectural product in the creation and reproduction of socio-spatial and socio-racial inequality yields the field of architectural practice exempt and blameless in its tangible contribution to the psychosocial and geospatial marginalization of communities of color, as in, for example, the case of gentrification. This paper attempts to illustrate the fact that architecture, like all of the built physical environment, is not ahistorical, apolitical – and certainly not race neutral – but, as a social product, is also understood clearly within these contexts, and its psychological and social impacts and outcomes must be examined with a racially critical lens, particularly in heterogeneous urban communities

STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function

Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers

Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD81 T-cell memory formation and function

Background The capacity of CD8+ T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T-cell immunity in human subjects is unknown. Objective We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Methods Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8+ T-cell differentiation in vivo and in vitro. Results Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8+ T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21–stimulated naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R–deficient subjects.Supported by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (to E.K.D., S.G.T., C.S.M., D.A.F., and M.C.C.), Cancer Council NSW (to S.G.T. and U.P.), and Rockefeller University Center for 541 Clinical and Translational science (5UL1RR024143, to J.-L.C.). C.S.M. is a recipient of a Career Development Fellowship and S.G.T. is a recipient of a Principal Research Fellowship from the NHMRC of Australia. Disclosure of potential conflict of interest: C. S. Ma has been supported by one or more grants from the National Health and Medical Research Council of Australia (NHMRC). J. Peake has received one or more payments for lecturing on allergy topics and has been reimbursed for travel/accommodations/meeting expenses. M. A. French has received one or more payments for lecturing from or is on the speakers’ bureau for ViiV Australia, MSD Australia, and Janssen Australia and has received one or more payments for travel/accommodations/meeting expenses from MSD Australia and ViiVAustralia. J.-L. Casanova has been supported by one or more grants from the National Institutes of Health (grant no. 8UL1TR000043); has consultancy arrangements with Regeneron, GlaxoSmithKline, NovImmune, BiogenIdec, Merck, and Sanofi- Aventis; and has received one or more grants from or has one or more grants pending with Merck. S. G. Tangye has been supported by one or more grants from the NHMRC of Australia; has received support for travel from ESID, Keystone Symposia, and the Jeffrey Modell Foundation; and has received one or more fees for serving as an expert witness in a patent dispute. E. K. Deenick has been supported by one or more grants from NHMRC, has received one or more payments for travel/accommodations/meeting expenses from the Japanese Society for Immunology, and has received one or more paid honoraria as an Editor for Immunology and Cell Biology. The rest of the authors declare that they have no relevant conflicts of interest