Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development

Abstract

The cytokine thymic stromal lymphopoietin (TSLP) drives immature B cell development in vitro and may regulate T helper type 2 responses. Here we analyzed the involvement of TSLP in B cell development in vivo with a doxycycline-inducible, keratin 5-driven transgene encoding TSLP (K5-TSLP). K5-TSLP-transgenic mice given doxycycline showed an influx of immature B cells into the periphery, with population expansion of follicular mature B cells, near-complete loss of marginal zone and marginal zone precursor B cells, and 'preferential' population expansion of peritoneal B-1b B cells. These changes promoted cryoglobulin production and immune complex-mediated renal disease. Identical events occurred in mice without T cells, in alternative TSLP-transgenic models and in K5-TSLP-transgenic mice with undetectable systemic TSLP. These observations suggest that signals mediating localized TSLP expression may modulate systemic B cell development and promote humoral autoimmunity.

Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis

“…26,29 We reported recently that TSLP mediates an increase in pre-B cell clonal expansion. 32 Additional experiments are required to determine whether imatinib directly affects this pre-B cell expansion versus exerting its negative effects at an earlier stage in B lymphopoiesis. Our findings do not rule out a potential, concurrent role for imatinib in modulating the survival of immature and mature B cells upon entry into the peripheral lymphoid compartment.…”

“…This blockade thereby reduced TSLP-driven pre-B cell expansion, 32 leading, ultimately, to an overall reduction in the exodus of B220 ϩ AA4.1 ϩ B cells from the marrow and subsequent generation of FM B cells.…”

“…32 This change occurs through a direct effect of TSLP via promotion of pre-B cell clonal expansion. Both strains exhibit an increase in the exodus of immature, B220 ϩ AA4.1 ϩ B cells from the BM and accumulation of large numbers of immature transitional 1 (T1) and naive follicular mature (FM) B cells within the spleen.…”

“…In parallel, sustained elevation in systemic levels of TSLP also leads to a near complete disappearance of splenic marginal zone (MZ) and marginal zone precursor (T2/MZP) B cells. 32 We isolated spleens from control vehicle-treated versus imatinib-treated WT or TSLP-Tg mice and analyzed the composition of the splenic B cell compartment including total B220 ϩ AA4 ϩ immature, FM, and MZ B cells by FACS. In WT mice, imatinib-treatment led to a modest reduction in the total number of splenic B cells, and this change reflected a numerical decrease in both immature, AA4 ϩ and mature, FM B cells.…”

Genomic profiling of high-risk acute lymphoblastic leukemia

“…70 CRLF2 forms a heterodimeric receptor with interleukin-7 receptor alpha for the cytokine thymic stromal lymphopoietin. [78][79][80] thymic stromal lymphopoietin/CRLF2 signaling has a role in dendritic cell development, 81 T cell responses, 82,83 allergic inflammation, [84][85][86] and promotes the proliferation of normal and leukemic B cells, [87][88][89][90][91] but at present the requirement for CRLF2 signaling in normal B-lymphoid ontogeny is unclear, and it may be dispensable. 88,92 The downstream mediators of thymic stromal lymphopoietin/CRLF2 signaling are poorly defined and may differ between human and mouse, and activation of JAK-STAT signaling has been described for the human but not CRLF2.…”