SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation.
SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation.
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DOI：
10.1084/jem.20052097
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发表时间：
2006-06-12
期刊：
影响因子：
--
通讯作者：
Schwartzberg PL
中科院分区：
文献类型：
--
作者：
Cannons JL;Yu LJ;Jankovic D;Crotty S;Horai R;Kirby M;Anderson S;Cheever AW;Sher A;Schwartzberg PL
X连锁淋巴增殖性疾病是由影响SH2D1A/SAP的突变引起的，SH2D1A/SAP是一种将Fyn募集到信号淋巴细胞激活分子（SLAM）相关受体的衔接蛋白。感染后，SLAM相关蛋白（SAP）缺失的小鼠表现出T细胞激活增加和体液免疫应答受损。尽管SAP缺失的小鼠能够对非T细胞依赖性免疫产生反应，但我们发现其初次和再次T细胞依赖性应答受损，伴有B细胞增殖、生发中心形成和抗体产生缺陷。然而，野生型而非SAP缺陷型的CD4细胞的转移挽救了重组激活基因2缺失和SAP缺失小鼠的体液免疫应答。为了研究这些T细胞缺陷，我们在体外和体内检测了CD4细胞的功能。尽管SAP缺陷型的CD4细胞在体外具有T细胞受体介导的T辅助（Th）2细胞因子产生受损，但我们证明在体内体液免疫缺陷可与细胞因子表达缺陷无关。相反，SAP缺陷型T细胞表现出诱导性共刺激分子（ICOS）诱导减少且延迟以及CD40L表达升高。值得注意的是，与Th2细胞因子缺陷相反，通过用SAP - R78A（一种损害Fyn结合的SAP突变体）进行逆转录病毒重建，挽救了体液免疫应答、ICOS表达和CD40L的下调。我们进一步证明了SLAM/SAP信号在早期表面CD40L表达调控中的作用。因此，SAP通过与其在细胞因子调控中的作用不同的机制影响T - B细胞协作所需关键分子的表达。
X-linked lymphoproliferative disease is caused by mutations affecting SH2D1A/SAP, an adaptor that recruits Fyn to signal lymphocyte activation molecule (SLAM)-related receptors. After infection, SLAM-associated protein (SAP)−/− mice show increased T cell activation and impaired humoral responses. Although SAP−/− mice can respond to T-independent immunization, we find impaired primary and secondary T-dependent responses, with defective B cell proliferation, germinal center formation, and antibody production. Nonetheless, transfer of wild-type but not SAP-deficient CD4 cells rescued humoral responses in reconstituted recombination activating gene 2−/− and SAP−/− mice. To investigate these T cell defects, we examined CD4 cell function in vitro and in vivo. Although SAP-deficient CD4 cells have impaired T cell receptor–mediated T helper (Th)2 cytokine production in vitro, we demonstrate that the humoral defects can be uncoupled from cytokine expression defects in vivo. Instead, SAP-deficient T cells exhibit decreased and delayed inducible costimulator (ICOS) induction and heightened CD40L expression. Notably, in contrast to Th2 cytokine defects, humoral responses, ICOS expression, and CD40L down-regulation were rescued by retroviral reconstitution with SAP-R78A, a SAP mutant that impairs Fyn binding. We further demonstrate a role for SLAM/SAP signaling in the regulation of early surface CD40L expression. Thus, SAP affects expression of key molecules required for T–B cell collaboration by mechanisms that are distinct from its role in cytokine regulation.
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DOI：
10.1084/jem.192.3.337
发表时间：
2000-08-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Parolini S;Bottino C;Falco M;Augugliaro R;Giliani S;Franceschini R;Ochs HD;Wolf H;Bonnefoy JY;Biassoni R;Moretta L;Notarangelo LD;Moretta A
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影响因子：
64.8
作者：
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通讯作者：
Ahmed, R
影响因子：
20.3
作者：
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通讯作者：
de Bracco, MM
DOI：
10.1084/jem.20040526
发表时间：
2004-07-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hron JD;Caplan L;Gerth AJ;Schwartzberg PL;Peng SL
通讯作者：
Peng SL