After antigen-driven expansion, the majority of T cells involved in an immune response die rapidly by apoptosis dependent on the Bcl-2 related proteins, Bim and Bax or Bak. The details of how these proteins are activated and interact are still unclear. The crystal structure of mouse Bcl-x(L) bound to a long helical fragment of Bim indicates that the structure of Bim is very different from proteins with a Bcl-2-like fold and may leave the BH3 region of Bim constitutively exposed. Based on the structural homology between Bcl-x(L) and Bax, we predicted that binding of Bim to Bax would require displacement of the Bax penultimate alpha helix. Consistent with this prediction, truncation of this short helix was required for Bim/Bax interaction and led to spontaneous activation of Bax. Our results suggest a way in which both Bim and Bax/Bak might be required for activated T cell apoptosis.

Posttranslational modifications of histones regulate chromatin structure and gene expression. Histone demethylases, members of a newly emerging transcription-factor family, remove methyl groups from the lysine residues of the histone tails and thereby regulate the transcriptional activity of target genes. JmjC-domain-containing proteins have been predicted to be demethylases. For example, the JmjC-containing protein JMJD2A has been characterized as a H3-K9me3- and H3-K36me3-specific demethylase. Here, structures of the catalytic-core domain of JMJD2A with and without alpha-ketoglutarate in the presence of Fe2+ have been determined by X-ray crystallography. The structure of the core domain, consisting of the JmjN domain, the JmjC domain, the C-terminal domain, and a zinc-finger motif, revealed the unique elements that form a potential substrate binding pocket. Sited-directed mutagenesis in conjunction with demethylase activity assays allowed us to propose a molecular model for substrate selection by the JMJD2 histone demethylase family.

Alpha/beta T cell receptors (TCRs) react with major histocompatibility complex proteins (MHC) plus peptides, a poorly understood phenomenon, probably because thymocytes bearing TCRs that manifest MHC-reactivity too well are lost by negative selection. Only TCRs with attenuated ability to react with MHC appear on mature T cells. Also, the interaction sites between TCRs and MHC may be inherently flexible and hence difficult to spot. Contacts between TCRs and MHC in the solved structures of their complexes were reevaluated with these points in mind. The results show that frequently used amino acids in TCR CDR1 and CDR2 regions are often used to bind MHC, in areas around small amino acids on the surfaces of MHC α helices that form a cup, allowing somewhat flexible binding of the TCRs. The TCR amino acids involved are specific to families of V regions and partially different rules govern recognition of MHC1 versus MHCII. TermsT cell receptor; MHC; evolution; conserved interactions; tolerance; selection; major histocompatibility complex A HISTORICAL INTRODUCTIONIt is almost 50 years since the discovery that the thymus had something to do with immune responses. Shortly thereafter, cells derived from the thymus were found to improve the ability of B cells to make antibodies, This was followed by the discovery of the carrier effect, i.e. the observation that the antibody response to haptens requires simultaneous recognition of both the hapten and epitopes on the attached protein carrier. These findings dovetailed unexpectedly well to give rise to the idea that T cells created in the thymus react with one portion of the antigen and then help B cells make antibody against a different determinant on the same molecule (1-4). This satisfying explanation for cell cooperation in NIH Public Access Author ManuscriptAnnu Rev Immunol. Author manuscript; available in PMC 2011 September 1.Published in final edited form as: Annu Rev Immunol. 2008 ; 26: 171-203. doi:10.1146/annurev.immunol.26.021607.090421. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptimmune responses left unresolved one key problem for immunologists, the problem of the major histocompatibility complex.The fact that the major histocompatibility complex (MHC) represents a special case for immune responses had been recognized many years before, by people studying the rejection of grafts and tumors (5, 6). They found that differences at the MHC were recognized by the immune system extraordinarily rapidly. This phenomenon led Niels Jerne to propose that lymphocyte receptors, by which, at the time, he meant immunoglobulin proteins, had evolved evolutionary to react with alleles of the MHC (7). In a ground breaking theoretical paper, he suggested that lymphocytes developing in the thymus somatically mutate their evolutionarily generated receptors such that the receptors no longer react with the MHC of their host, but retain the ability to react well with MHC of others.Meanwhile, others were beginning to realize that T and B cells do not re...