gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis.
Integrins contribute to lymphopoiesis, whereas Toll-like receptors (TLRs) facilitate the myeloid replenishment during inflammation. The combined role of TLRs and integrin on hematopoiesis remains unclear. gp96 (grp94, HSP90b1) is an endoplasmic reticulum master chaperone for multiple TLRs. We report herein that gp96 is also essential for expression of 14 hematopoietic system-specific integrins. Genetic deletion of gp96 thus enables us to determine the collective roles of gp96, integrins, and TLRs in hematopoiesis. We found that gp96-null hematopoietic stem cells could support long-term myelopoiesis. B- and T-cell development, however, was severely compromised with transitional block from pro-B to pre-B cells and the inability of thymocytes to develop beyond the CD4(-)CD8(-) stage. These defects were cell-intrinsic and could be recapitulated on bone marrow stromal cell culture. Furthermore, defective lymphopoiesis correlated strongly with failure of hematopoietic progenitors to form close contact with stromal cell niche and was not the result of the defect in the assembly of antigen receptor or interleukin-7 signaling. These findings define gp96 as the only known molecular chaperone to specifically regulate T- and B-cell development.
Staron
Matthew
M
Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.
Yang
Yi
Y
Liu
Bei
B
Li
Janet
J
Shen
Yuankai
Y
Zúñiga-Pflücker
Juan Carlos
JC
Aguila
Hector L
HL
Goldschneider
Irving
I
Li
Zihai
Z
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D019070:Cell Lineage / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D016023:Integrins / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D038042:Myelopoiesis / Q000502:physiology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology; D051193:Toll-Like Receptors / Q000378:metabolism
D016023:Integrins; D015851:Interleukin-7; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051193:Toll-Like Receptors; C053387:endoplasmin