Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Nat Immunol. 2021 Mar;22(3):381-390. doi: 10.1038/s41590-021-00862-z. Epub 2021 Feb 15.
The integrin αβ selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of αβ surface expression and gut immunity. Shp1 selectively inhibited β endocytosis, enhancing surface αβ display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin β on the cell surface to target intracellular Shp1 to β. Shp1 restrained plasma membrane β phosphorylation and inhibited β endocytosis without affecting β integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface αβ and in homing to GALT. Consistent with the specialized role of αβ in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.
整合素 αβ 选择性调节肠道和肠道相关淋巴组织（GALT）中的淋巴细胞迁移和黏附。在这里，我们描述了酪氨酸磷酸酶 Shp1 和 B 细胞凝集素 CD22（Siglec-2）在调节 αβ 表面表达和肠道免疫中的意外作用。Shp1 选择性地抑制 β 内吞作用，增强 αβ 的表面表达和淋巴细胞归巢至 GALT。在 B 细胞中，CD22 以唾液酸依赖性方式与细胞表面的整合素 β 结合，将细胞内的 Shp1 靶向到 β。Shp1 抑制质膜 β 磷酸化并抑制 β 内吞作用，而不影响 β 整合素。Shp1 活性降低、缺乏 CD22 或表达 CD22 结合 Shp1 或碳水化合物结合结构域突变的 B 细胞，其表面 αβ 和归巢至 GALT 的水平均平行降低。与 αβ 在肠道免疫中的特殊作用一致，CD22 缺陷选择性抑制肠道抗体和病原体反应。
