T-lymphocyte activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-cell immune responses. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals. To understand the role of ICOS in T-cell activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-cell activation and proliferation are defective in the absence of ICOS. In addition, ICOS -/- T cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.

Mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs.

The development of lymphoid organs can be viewed as a continuum. At one end are the 'canonical' secondary lymphoid organs, including lymph nodes and spleen; at the other end are 'ectopic' or tertiary lymphoid organs, which are cellular accumulations arising during chronic inflammation by the process of lymphoid neogenesis. Secondary lymphoid organs are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoid organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations. Between these two boundaries are other types of lymphoid tissues that are less developmentally but more environmentally regulated, such as Peyer's patches, nasal-associated lymphoid tissue, bronchial-associated lymphoid tissue and inducible bronchial-associated lymphoid tissue. Their regulation, functions and potential effects are discussed here.

Lymphotoxin alpha (LT alpha)-deficient mice revealed critical roles for LT alpha in lymphoid organogenesis, but it is not clear whether LT alpha functions through an LT alpha homotrimer (LT alpha3) or LT alpha/beta heterotrimers. We generated LTbeta-deficient mice and found them to lack Peyer's patches, peripheral lymph nodes, splenic germinal centers, and follicular dendritic cells. Unlike LT alpha-deficient mice, LT beta-deficient mice had cervical and mesenteric lymph nodes. Furthermore, the mesenteric lymph nodes had germinal center-like regions, although these structures appeared to lack follicular dendritic cells. The absence of cervical and mesenteric lymph nodes in LT alpha-deficient mice, and yet their presence in LT beta-deficient mice and in mice deficient in tumor necrosis factor receptor types I and II, suggest that LT alpha3 may signal via an as yet unidentified receptor.

Summary Cloned CD4 T cell lines that recognize the Ac1-16 peptide of myelin basic protein bound to I-A" were isolated and used to analyze the immunopathogeuesis of experimental autoimmune encephalomyelitis (EAE). T helper type 1 (Thl) clones induced disease, while Th2 clones did not. Using variants of a single cloned Thl line, the surface expression of o~4 integrins (very late antigen 4 [VLA-4]) was identified as a major pathogenic factor. Encephalitogenic clones and nonencephalitogenic variants differ by 10-fold in their level of surface expression of a4 integrin and in their ability to bind to endothelial cells and recombinant vascular cell adhesion molecule 1 (VCAM-1). The cx4 integrin-high, disease-indudng cloned Thl T cells enter brain parenchyma in abundance, while ~x4 integrin-low, nonencephalitogeuic Thl cells do not. Moreover, antibodies to o~4 integrin, its ligand VCAM-1, and intercellular adhesion molecule 1 all influence the pathogenicity of this eucephalitogenic clone in vivo. The importance of the expression of VLA-4 for encephalitogenicity is not unique to cloned T cell lines, as similar results were obtained using myelin basic protein-primed lymph node T cells, o~4 integrin levels did not affect antigen responsiveness or production of the Thl cytokines interleukin 2, interferon 7, and lymphotoxin/tumor necrosis factor fl; and antibodies against o~4 integrin did not block antigen recognition in vitro. Thus, we conclude that surface expression of oe4 integrin is important in CD4 T cell entry into brain parenchyma. A general conclusion of these studies is that or4 integrins may be crucial in allowing activated effector T cells to leave blood and enter the brain and other tissues to clear infections.