Cellular source and molecular form of TNF specify its distinct functions in organization of secondary lymphoid organs

Abstract

IntroductionSecondary lymphoid organs provide an important microenvironment for the initiation and development of efficient immune responses. Their highly sophisticated structure allows migration and interactions between antigen-presenting cells, T and B lymphocytes, as well as follicular dendritic cells (FDCs) and other stromal cells. The cooperation of the lymphoid cells within secondary lymphoid organs dramatically increases the probability of interactions of rare B, T, and antigen-presenting cells that result in effective generation of humoral immune responses (reviewed in Fu and Chaplin, 1 Mebius, 2 and Allen et al 3 ).Tumor necrosis factor (TNF) and lymphotoxin (LT) are cytokines required for both formation and maintenance of the microarchitecture of the secondary lymphoid organs, acting primarily through their receptors TNFRp55 and LT␤R, respectively, and engaging classical and alternative nuclear factor-B (NF-B) pathways. 1,4,5 In vivo TNF is produced by many cell types, including lymphoid and stromal cells, and can exist in membranebound as well as in soluble forms. 6 Systemic TNF ablation in mice results in the impairment of humoral immune responses, host defense functions, and in multiple defects in lymphoid tissues including disruption of primary B-cell follicles and absence of germinal centers (GCs) and FDCs. [6][7][8][9][10] FDCs are key components in the dynamic organization of the germinal center structure and are essential for generation of efficient immune responses as well as for support of follicular microarchitecture and migration of B cells to the follicles. 3,[11][12][13] Accordingly, mice that lack FDCs show reduced specific immunoglobulin G (IgG) antibody responses to T-cell-dependent antigens. 1,5 Several studies addressed TNF-and LT-dependent mechanisms that may regulate the generation of FDCs and B-cell follicles in different secondary lymphoid organs. 14,15 In particular, in contrast to the spleen, the generation of FDCs in lymph nodes (LNs) and PP is independent of surface LT expression by B and T cells. 4,15 While the critical role of B-cell-derived TNF and LT for development of FDCs and B-cell follicles in spleen has been well established, 1,16,17 the contribution of various TNF-producing cells in organization of secondary lymphoid organs other than spleen remains unknown.To define the role of TNF produced by specific cell types in development and maintenance of secondary lymphoid organs, we used mice with conditional inactivation of TNF gene restricted to either B cells (B-TNF knockout [KO]) or T cells (T-TNF KO) or to both T cells plus B cells (T,B-TNF KO). Some of these mice were also crossed to mutant mice expressing only membrane-bound TNF 18 to distinguish between 2 molecular forms of TNF produced by a given cellular source. Our results obtained using this experimental panel unravels distinct contributions of TNF signals originating from B and T cells to the maintenance of distinct lymphoid tissues, such as spleen, LNs, and Peyer patches (PPs), and to the efficiency of humor...

T cell killing by tolerogenic dendritic cells protects mice from allergy

“…In mice, the deficiency for TNF or TNF receptors interferes with the formation of B cell follicles, follicular DC networks, and germinal centers in secondary lymphoid organs (13,14). We therefore performed anti-TNF antibody studies, which showed that neutralization of TNF during the effector phase of LZT but not during the induction phase of LZT significantly inhibited the development of LZT (Supplemental Figure 3, A and B).…”

Re-thinking the functions of IgA+plasma cells

“…[141][142][143] Importantly, B cellderived TNFa is critical for the formation of FDC networks, GC and B cell follicles in the spleen, while TNFa from B and T cells synergizes for GC and FDC networks in LN, which is critical for the generation of local immune responses. 144,145 Moreover, maintenance of long-lived PC in BM is thought to require a specialized niche that mediates their survival at least partially through TNFa. 146 Lastly, full maturation of ILF requires TNFRI, 21 and B cell-derived TNFa was also shown to regulate GC in PP.…”

Pathogenic and Protective Functions of TNF in Neuroinflammation Are Defined by Its Expression in T Lymphocytes and Myeloid Cells

“…Our findings link protective and pathogenic effects of TNF in CNS autoimmunity to specific cellular sources and suggest that the balance between the effects of TNF in the target organ and peripheral lymphoid tissues is crucial for the final outcome of the disease. -TNF KO; TNF flox/flox CD19-Cre), as well as the TNF KO mice, used in this study were described elsewhere (14,17). Concomitant ablation of TNF in both T cells and myeloid cells (MT-TNF KO; TNF flox/flox MlysCre CD4-Cre) was achieved by crossing M-TNF KO and T-TNF KO mice.…”