Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.
Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.
复制标题
DOI：
10.1084/jem.185.12.2111
复制
发表时间：
1997-06-16
期刊：
影响因子：
--
通讯作者：
Chaplin DD
中科院分区：
文献类型：
--
作者：
Fu YX;Molina H;Matsumoto M;Huang G;Min J;Chaplin DD
LTα-缺陷（LTα−/−）小鼠脾脏微结构发生改变。这包括失去正常的B细胞- t细胞区隔，滤泡树突状细胞（FDC）簇，以及形成生发中心（GC）的能力。用绵羊红细胞（SRBC）免疫的LTα - / -小鼠在原发性或继发性反应中产生高水平的抗原特异性IgM，但没有IgG，表明Ig类转换失败。这种无法转换为IgG可能是由于这些小鼠脾脏微结构的改变。或者，这可能是直接由于淋巴细胞在抗体反应中合作对LTα表达的要求。为了研究这一点，我们进行了反向脾细胞转移。用野生型脾细胞重建LTα - / -小鼠后，立即用SRBC免疫，脾脏微结构仍然受到干扰，IgG无应答。相比之下，当野生型动物接受来自LTα−/−小鼠的脾细胞照射时，卵泡结构和强烈的IgG反应被保留。这些数据表明，缺乏lt α-的B细胞和T细胞在产生IgG应答的能力上没有内在缺陷。相反，LTα - / -小鼠的微环境特征的改变似乎导致切换到生产性IgG反应的能力受损。为了研究长期表达LTα是否会改变脾滤泡的结构和功能，我们采用骨髓移植。野生型BM重建LTα−/−小鼠6周后，脾脏滤泡结构部分恢复，FDC簇和GC返回。B细胞/T细胞区隔异常，白色髓区小。这伴随着IgG对SRBC应答的恢复。LTα−/−BM野生型小鼠的重组导致FDC簇和GC的丢失，以及IgG应答的丢失，尽管区隔的B细胞和T细胞区在很大程度上保留了下来。因此，有缺陷的IgG产生与异常的B细胞和T细胞区隔化并不绝对相关。相反，LTα的表达支持脾脏卵泡结构的成熟，包括FDC簇的发育和维持，这支持Ig类转换和有效的IgG应答。
LTα-deficient (LTα−/−) mice show altered splenic microarchitecture. This includes loss of normal B cell–T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTα−/− mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTα expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTα−/− mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTα−/− mice, follicle structure and a strong IgG response were retained. These data indicate that LTα-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTα−/− mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTα could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTα−/− mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTα−/− BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTα supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.