Dendritic Cells and Nature of T-Cell Help

27 October, 1998

Dendritic Cells and Nature of T-Cell Help

Once a neglected and obscure cell type, dendritic cells (DCs) can now be readily obtained in sufficient quantities to allow the analysis of their functions at molecular and cellular levels. These cells are also emerging as a powerful tool for manipulating the immune system.
In a brief review, DCs capture antigens in peripheral tissues and process them to form MHC-peptide complexes. Immature DCs derive successively from proliferating progenitors and also from non-proliferating uncommitted precursors. Upon antigen deposition, DCs begin to mature and migrate to lymphoid organs, the spleen and the lymph node, while expressing molecules that lead to binding and stimulation of T cells in the T-cell areas of lymphoid tissues. If the same antigen is also found bound by B cells, B cells can cluster with DCs. After activation, T and B blasts leave the T-cell areas. B blasts move to the lining of the intestine, the bone marrow, and other parts of the lymphoid tissue (medulla of lymph node, etc) and some B blasts become antibody-secretin plasma cells. T blasts go through the thoracic duct and blood and respond to cells that are presenting antigen at the antigen deposition site. The T-cell response is limited to the site of microbial infection, inflammation and tumors. Thus T and B lymphocytes are the mediators of immunity but their function is in a way under the control of DCs (Banchereau J and Steinman RM, 1998: uid=98180615).

CD8+ cytotoxic T-cells (CTLs) are primed, or differentiated from naive CD8+ T cells, by the participation of CD4+ T-helper cells but the nature of this 'help' was unknown. One notion is that help for CTLs is mediated directly by cytokines produced by T-helper cells proximally present on antigen-presenting cells (APCs). An alternative idea is that help is indirect through activation of APCs first, which then prime CTLs. Since CTLs and T-helper cells can not detect each other's presence, they should be brought together by antigen-loaded dendritic cells that display antigens to both. CD40 (CD154 or gp39) expressed on the surface of APCs (DCs, macrophages, B cells) interacts with CD40L ligand molecule expressed on activated CD4+ T-cells. In fact, modulation (ligation) of CD40 greatly increases APC's antigen-presentation and costimulatory capacity and can bypass help from T-helper cells in priming CTLs. Responses to some virus infection are also helper-independent and infected DCs can stimulate CTLs without T-helper cells. The hypothesis arises here that T-helper cells first 'condition' DCs, which then become empowered to stimulate (prime) CTLs. This would enable the eventual interaction of 3 cell types (T-helper, APC, CTL) that are rare and migratory in the body (Ridge JP et al. 1998: uid=98285484; Bennett SR et al. 1998: uid=98285485; Schoenberger SP et al. 1998: uid=98285486).

As seen above, CD40 signalling, or CD40-CD40L interaction, is important in humoral and cell-mediated immune responses. It is also suspected that CD40L+ T-cells are somehow involved in the atherogenesis due to its accumulation in atheroma. Anti-CD40L antibody prevents experimental autoimmune diseases such as collagen-induced arthritis and multiple sclerosis, whereas ligation of CD40 on atheroma-associated cells induces atherogenesis-related activities such as inflammatory cytokines, matrix metalloproteinases and adhesion molecules. It has now been reported (Mach F et al. 1998: uid=98334381) that anti-CD40L antibody reduced the size of aortic atherosclerotic lesions by 59% and their lipid content by 79% in mice fed with a high-cholesterol diet for 12 weeks. Significantly fewer macrophages and T-cells were also found in atheroma. These results indicate a role for CD40 signalling for atherogenesis.

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