The genes encoding the alpha and beta chain of the T-cell receptor and the gamma gene have been cloned, and their structure, organization, ontogeny of expression, pattern of rearrangement, and diversification are now generally understood. In most cases, the immunoglobulin paradigm applied very well to the corresponding phenomena in T cells, although as described above, some interesting and potentially important differences exist. Nevertheless, there are still many unanswered questions regarding the ontogeny and mechanism of MHC-restricted antigen recognition, and it is not clear how far the immunoglobulin model can take us in understanding these phenomena. Although the alpha/beta heterodimer looks like an antibody and the binding sites of the two molecules may be similar, the rules governing B- and T-cell activation are clearly different, and the ligand(s) bound by the receptor are still poorly characterized. In the future, T-cell receptor genes, as well as those encoding the T-cell accessory molecules, will be altered in vitro and transferred into mammalian cells in culture and into whole organisms in an attempt to understand T-cell antigen recognition. These tools will allow us to manipulate the mammalian immune response in a variety of different ways that will have a profound impact both on our understanding of immunology and on medicine in the future.

Butyrophilin-like 2 (BTNL2) is a butyrophilin family member with homology to the B7 costimulatory molecules, polymorphisms of which have been recently associated through genetic analyses to sporadic inclusion body myositis and sarcoidosis. We have characterized the full structure, expression, and function of BTNL2. Structural analysis of BTNL2 shows a molecule with an extracellular region containing two sets of two Ig domains, a transmembrane region, and a previously unreported cytoplasmic tail. Unlike most other butyrophilin members, BTNL2 lacks the prototypical B30.2 ring domain. TaqMan and Northern blot analysis indicate BTNL2 is predominantly expressed in digestive tract tissues, in particular small intestine and Peyer’s patches. Immunohistochemistry with BTNL2-specific Abs further localizes BTNL2 to epithelial and dendritic cells within these tissues. Despite its homology to the B7 family, BTNL2 does not bind any of the known B7 family receptors such as CD28, CTLA-4, PD-1, ICOS, or B and T lymphocyte attenuator. Because of its localization in the gut and potential role in the immune system, BTNL2 expression was analyzed in a mouse model of inflammatory bowel disease. BTNL2 is overexpressed during both the asymptomatic and symptomatic phase of the Mdr1a knockout model of spontaneous colitis. In functional assays, soluble BTNL2-Fc protein inhibits the proliferation of murine CD4+ T cells from the spleen, mesenteric lymph node, and Peyer’s patch. In addition, BTNL2-Fc reduces proliferation and cytokine production from T cells activated by anti-CD3 and B7-related protein 1. These data suggest a role for BTNL2 as a negative costimulatory molecule with implications for inflammatory disease.

We have analysed 19 complementary DNA clones encoding the alpha-chain of the T-cell antigen receptor derived from thymic transcripts, and find that 15 of them contain partial or complete variable (V alpha) genes. Seven of these genes cross-hybridize to over 40 germline V alpha gene segments in Southern blot analyses. Of the 19 joining (J alpha) sequences examined, 18 seem to be encoded by distinct gene segments, hence the repertoire of J alpha gene segments is much larger than those of the immunoglobulin or T-cell receptor beta-chain gene families. We suggest that the variable domains of immunoglobulins and T-cell antigen receptors are similar in structure.

We have analyzed the control of developmental expression of the CD4 gene, which encodes an important recognition molecule and differentiation antigen on T cells. We have determined that the CD4 promoter alone functions at high levels in the CD4+ CD8-mature T cell but not at the early CD4+ CD8+ stage of T-cell development. In addition, the CD4 promoter functions only in T lymphocytes; thus, the stage and tissue specificity of the CD4 gene is mediated in part by its promoter. We have determined that a Myb transcription factor binds to the CD4 promoter and is critical for full promoter function. Thus, Myb plays an important role in the expression of T-cell-specific developmentally regulated genes.The CD4 glycoprotein is expressed on specific subsets of mature T cells and thymocytes and plays an important role both in T-cell antigen-specific activation and in T-cell development (37,47). T cells are capable of recognizing antigen only in the form of an oligopeptide bound to a membrane protein encoded within the major histocompatibility complex (MHC) (for a review, see reference 22). The antigenspecific and MHC allele-specific interaction is mediated primarily by the T-cell antigen receptor, whereas CD4 and CD8, another glycoprotein similar in function to CD4, recognize nonpolymorphic regions of the MHC molecule (10, 55). This latter interaction serves both to increase the affinity of the T cell for the antigen-presenting cell (APC) and to provide additional stimulatory signals via the tyrosine kinase pS6Ick (49). CD4 binds to MHC class II molecules and is expressed only on T cells bearing MHC class II-restricted T-cell antigen receptors (TCRs), primarily helper T (TH) cells (66). Thus, CD4 plays an important role in specifying T-cell antigen/MHC recognition and may also influence T-cell functional subclass.CD4 also plays a critical role in T-cell development. Immature thymocytes initially do not express TCR, CD4, or CD8. These CD4-CD8-(double-negative) cells differentiate to express high levels of all three molecules, forming TCR+ double-positive (CD4+ CD8+) cells that compose the largest thymocyte subpopulation (12,70). CD4+ CD8+ thymocytes that bind MHC class II molecules via the TCR and CD4 downregulate the expression of CD8 and maintain the expression of CD4; conversely, thymocytes that ligate MHC class I molecules via the TCR and CD8 molecules downregulate CD4 and maintain CD8 expression (2,29,31,58,59). This process of selection results in the mature TCR+ singlepositive (CD4+ CD8-and CD4-CD8+) populations that seed the peripheral lymphoid organs.

It has been postulated that the variable region of the beta-polypeptide of the murine T-cell antigen receptor is encoded by three distinct germ-line gene segments--variable (V beta), diversity (D beta) and joining (J beta)--that are rearranged to generate a V beta gene. Germ-line V beta and J beta gene segments have been isolated previously. Here we report the isolation and characterization of two germ-line D beta gene segments that have recognition signals for DNA rearrangement strikingly similar to those found in the three immunoglobulin gene families and in V beta and J beta gene segments. The D beta and J beta segments can join in the absence of V beta gene segment rearrangement and these rearranged sequences are transcribed in some T cells.