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Casitas B cell lymphoma (Cbl) proteins are negative regulators for T cell antigen receptor (TCR) signaling. Their role in thymocyte development remains unclear. Here we show that simultaneous inactivation of c-Cbl and Cbl-b in thymocytes enhanced thymic negative selection and altered the ratio of CD4 + and CD8 + T cells. Strikingly, the mutant thymocytes developed into CD4 + ...
Although Toll-like Receptors (TLRs) play a major function in innate recognition of pathogens, their role in antigen processing and presentation in vivo is poorly understood. Here we establish that Toxoplasma gondii profilin, a TLR11 ligand present in the parasite, is an immunodominant antigen in the CD4 + T cell response to the pathogen. The immunogenicity of profilin was entirely dependent...
We used negative stain electron microscopy (EM) to examine the conformational changes in the ectodomains required for activation of the leukocyte integrins α X β 2 and α L β 2 . They transitioned between a bent conformation and two extended conformations in which the headpiece was in either a closed or an open state. Extended integrins exhibited marked flexibility at...
The major histocompatibility complex class I molecules display peptides (pMHC I) on the cell surface for immune surveillance by CD8 + T cells. These peptides are generated by proteolysis of intracellular polypeptides by the proteasome in the cytoplasm and then in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with antigen processing (ERAAP). To define the unknown mechanism...
Dendritic cells (DCs) initiate adaptive immune responses by activating T cells via cognate interactions between MHC-peptide complexes and T cell receptors. In immature DCs, MHC class II is predominantly stored in late endocytic compartments, where it has a short half-life because of degradation. In contrast, mature DCs recruit MHC class II to the plasma membrane. We here demonstrate that in immature...
Major histocompatibility complex (MHC) class II molecules present products of lysosomal proteolysis to CD4 + T cells. Although extracellular antigen uptake is considered to be the main source of MHC class II ligands, a few intracellular antigens have been described to gain access to MHC class II loading after macroautophagy. However, the general relevance and efficacy of this pathway is unknown...
The T cell immunoglobulin mucin (TIM) receptors are involved in the regulation of immune responses, autoimmunity, and allergy. Structures of the N-terminal ligand binding domain of the murine mTIM-1 and mTIM-2 receptors revealed an immunoglobulin (Ig) fold, with four Cys residues bridging a distinctive CC′ loop to the GFC β-sheet. The structures showed two ligand-recognition modes in the TIM family...
The αβ and γδ T lineages are thought to arise from a common precursor; however, the regulation of separation and development of these lineages is not fully understood. We report here that development of αβ and γδ precursors was differentially affected by elimination of ribosomal protein L22 (Rpl22), which is ubiquitously expressed but not essential for translation. Rpl22 deficiency selectively arrested...
T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B ∗ 0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B ∗ 4402 and HLA-B ∗ 4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B ∗ 0801, HLA-B ∗ 4402, and HLA-B...
Chemokines orchestrate immune cell trafficking by eliciting either directed or random migration and by activating integrins in order to induce cell adhesion. Analyzing dendritic cell (DC) migration, we showed that these distinct cellular responses depended on the mode of chemokine presentation within tissues. The surface-immobilized form of the chemokine CCL21, the heparan sulfate-anchoring ligand...
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