Talin1 is required for integrin-dependent B lymphocyte homing to lymph nodes and the bone marrow but not for follicular B-cell maturation in the spleen

Abstract

Talin1 is a key integrin coactivator. We investigated the roles of this cytoskeletal adaptor and its target integrins in B- IntroductionProper circulation of B lymphocytes between primary and secondary lymphoid organs is critical for their differentiation and function in the establishment of normal humoral protection. [1][2][3] In adult mice, B-cell precursors rearrange their immunoglobulin (Ig) genes and differentiate into immature B cells in the bone marrow (BM). 4,5 After negative selection, these cells egress from BM niches, enter the circulation, and home to the spleen where they reach final maturation or die. 6 Immature spleen B cells can develop into either marginal zone (MZ) B cells or follicular B cells based on signaling through the B-cell receptor, Notch2, and the canonical nuclear factor-B pathway. 7 MZ B cells are a sessile population that reside at the border between the white and red pulps, and respond vigorously to blood-borne T cell-independent antigens. 8 Follicular (FO) B cells are generated from immature B cells entering the white pulp 3 and that differentiate into transitional 1 (T1) and transitional 2 (T2) cells based on their surface phenotype and functional characteristics. 9,10 The T1 Ͼ T2 Ͼ FO pathway is considered the main B-cell differentiation pathway in the spleen and is critical for the ability of B cells to respond to blood-borne T-dependent antigens. 11 A fraction of the mature follicular B lymphocytes leave the spleen and circulate in peripheral lymph nodes and mucosal-associated lymphoid tissues. Subsets of spleen and lymph node B cells can also home back to the BM, mainly after encountering antigen, and they differentiate into plasma or memory subsets. 12 Similar to T-cell circulation through various lymphoid organs, the entry of B subsets into the BM, lymph nodes, and the spleen involves their crossing of different types of endothelial barriers. 13 A key checkpoint in this emigration of both T and B cells is their ability to firmly attach to and protrude through the endothelial cell barrier lining these organs. 14 Whereas leukocyte intravasation (egress) into blood 15 is thought to take place independently of integrin-ligand interactions, B lymphocyte extravasation from the blood is thought to be mediated by distinct integrin-ligand interactions that generate shear-resistant adhesions. 14,16 Nevertheless, once in the extravascular tissues, interstitial motility of B lymphocytes, like other leukocytes, is thought to take place independently of integrins via chemokine cues. 17,18 Accumulating studies have established a key role for 3 B-cell integrins, VLA-4 (␣4␤ 1 ), ␣ 4 ␤ 7 , and LFA-1 (␣ L ␤ 2 ) in the trafficking of mature B cells to lymph nodes, the BM, 19 and peripheral sites of inflammation. 20 Although LFA-1 has a key role in B-cell migration to peripheral lymph nodes and Peyer patches, 21 it plays redundant roles in lymphocyte entry to the spleen and its white pulp. 2,21 Similarly, although the roles of ␣ 4 integrins in B-cell trafficking to mucosal tissues and the BM a...

Zasp regulates integrin activation

“…Kindlin-mediated integrin activation appears to be talin dependent and integrin specific; co-expression of kindlin-1 or -2 with talin head enhances aIIbb3 activation (Ma et al, 2008;Montanez et al, 2008;Moser et al, 2009a;Moser et al, 2009b;Moser et al, 2008;Shattil et al, 2010), but kindlin-1 and -2 do not activate a5b1 integrins . Further, the loss of the hematopoietic kindlin-3 affects b2 and b3 (Manevich-Mendelson et al, 2010;Moser et al, 2009a) but not b1-mediated cell adhesion (Manevich-Mendelson et al, 2010). Here we show that unlike kindlins, which co-activate b3 integrins, Zasp specifically co-activates b1 and not b3 integrins.…”

An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

“…Notably, this resulted in a significant reduction of B cell migration to the bone marrow and lymph nodes but not to the spleen. Furthermore, these mice displayed a considerable defect in terms of an effective humoral response to peripherally introduced Tdependent antigen [45]. The absence of talin 1 in PBMCs from cuprizone-treated mice may thus indicate impaired integrin adhesion function of B cells.…”

“…The integrins, LFA-1 (αLβ2), VLA-4 (α4β1) and α4β7, are required for the migration of mature B cells from the blood to the bone marrow, lymph nodes and to peripheral sites of inflammation [43,44]. A recent study simultaneously inhibited the adhesive functions of these integrins by deleting the expression of talin 1 [45]. Notably, this resulted in a significant reduction of B cell migration to the bone marrow and lymph nodes but not to the spleen.…”

Talin1 Regulates Integrin Turnover To Promote Embryonic Epithelial Morphogenesis

“…Nonetheless, transfection of the talin1 Ϫ/Ϫ epiblast cells or EBs with human integrin ␤1 largely rescued cell spreading, FA adhesion assembly, and epiblast VOL. 31,2011 Talin1 REGULATES INTEGRIN TURNOVER 3375…”

“…In vivo, conditional deletion of the talin1 gene in mouse platelet precursors inhibited ligand-induced ␣IIb␤3 integrin activation and platelet aggregation, leading to impaired hemostasis in the whole animal (13,36,40). Similarly, in B-lymphocytes, talin1 is required for ␣4␤1 (VLA-4) and ␣ L ␤2 (LFA-1) integrin activation and thereby for homing to lymph nodes and bone marrow (31).…”