The interaction of antigen-specific T cell receptors (TCRs) with their ligands, peptides bound to molecules of the major histocompatibility complex (MHC), is central to most immune responses, yet little is known about its chemical characteristics. The binding to T cells of a labeled monoclonal antibody to the TCR was inhibited by soluble class II MHC heterodimers complexed to different peptides. Inhibition was both peptide- and TCR-specific and of low affinity, with a KD = 4 x 10(-5) to 6 x 10(-5) M, orders of magnitude weaker than comparable antibody-antigen interactions. This finding is consistent with the scanning nature of T cell recognition and suggests that antigen-independent adhesion precedes TCR engagement.

SummaryThe role of CD28-mediated signals in T helper cell maturation is not fully understood. We tested the requirement for costimulation through CD28 in several systems of CD4 + T cell differentiation. In vivo priming of mice with genetic disruption of CD28 (CD28 -/-) yielded normal levels of antigen-specific interferon ~/production but markedly diminished levels of interleukin 4 (IL-4) after in vitro restimulation. In response to the pathogenic microbe, Leishmania major, C57BL6 CD28 -/-mice were fully capable of controlling infection and exhibited a normal T helper 1 response. BALB/c CD28 -/-mice unexpectedly exhibited normal susceptibility to L. major. BALB/c CD28 -/-mice developed high levels oflL-4 mRNA and protein induction in the draining lymph nodes. In addition, susceptibility of BALB/c CD28 -/-mice was reversed by neutralization of IL-4 in vivo. We also activated transgenic CD28-bearing T cells from the BALB and C57BL background in vitro in the presence of CTLA4Ig. BALB cells had greater IL-4-producing capacity than C57BL cells in the absence of costimulation. Diverse factors including costimulatory signals, genetic polymorphism, and the nature of the immunogen all influence T helper phenotype commitment, but these results provide evidence that CD28 is not an absolute requirement for generating either Thl or Th2 responses.U 'nder most circumstances, successful T cell activation requires a signal delivered through the T cell antigen receptor and a second signal referred to as costimulation (1). T cells activated in vitro in the presence of CD28-B7 blockade display characteristics of anergy (2), and blockade in vivo has attenuated many T cell-mediated immune responses, including graft rejection (3, 4) and autoimnmnity (5-7). Analysis of CD28-deficient mice revealed relatively normal T cell development, preserved cytolytic T cell responses, but impaired B cell help (8). The role of costimulation in the generation and maintenance of antigen-specific CD4 + T helper (Th) subsets remains controversial. Data supports models in which both Thl and Th2 responses require CD28-mediated signals (2, 9-11), but some evidence suggests that only certain Th subsets are dependent on costimulation (12-20). Other findings suggest discrete stages of maturation selectively require CD28-mediated costimulation (12), and some current models propose that specific B7 ligands mediate biased Th maturation (5,6,21,22).Daniel R. Brown and Jonathan M. Green contributed equally to this work.In murine infection with Leishmania major, pathogenspecific CD4 + Th effectors mediate the polarized potential outcomes of infection (23). Thl responses that arise in C57BL/6 mice result in self-limited heating disease through successful macrophage activation by T cell-derived IFN-y. Th2 responses that arise in mice from the BALB background mediate inexorable susceptibility characterized by uncontrolled parasite dissemination. The unique localization of the parasite to MHC class II-rich intracellular compartments leads to a strong bias in CD4 +, clas...

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The XLR gene family consists of approximately 10 X-linked genes, the expression of which is regulated in lymphocyte development. Certain members of the gene family are closely linked to the murine xid immune deficiency mutation. Sequence analysis of a cDNA clone pM1 derived from the plasmacytoma MOPC167 showed an open reading frame capable of coding for a protein of 208 amino acids and mol wt 24,000. The lack of a signal peptide or transmembrane region indicates a probable cytoplasmic or nuclear localization for the predicted pM1 protein. The predicted protein shares significant homology with lamins A and C and other members of the intermediate filament family of proteins, and shares features important for the coiled-coil structure proposed for these proteins. Analysis of cDNA clones derived from a presecretory lymphoma and from adult thymus indicates that B and T lymphocytes transcribe a common major mRNA identical to pM1, while other rare transcripts were also identified by these studies. A series of clonal T lymphoma lines representing distinct stages of thymic differentiation showed that, as with B lymphoid tumors, XLR expression is correlated with the maturation of the thymomas.