TCR-induced transmembrane signaling by peptide/MHC class II via associated Ig-alpha/beta dimers.

Previous findings suggest that during cognate T cell-B cell interactions, major histocompatability complex (MHC) class II molecules transduce signals, leading to Src-family kinase activation, Ca2+ mobilization, and proliferation. Here, we show that antigen stimulation of resting B cells induces MHC class II molecules to associate with Immunoglobulin (Ig)-alpha/Ig-beta (CD79a/CD79b) heterodimers, which function as signal transducers upon MHC class II aggregation by the T cell receptor (TCR). The B cell receptor (BCR) and MHC class II/Ig-alpha/Ig-beta are distinct complexes, yet class II-associated Ig-alpha/beta appears to be derived from BCR. Hence, Ig-alpha/beta are used in a sequential fashion for transduction of antigen and cognate T cell help signals.

Ligation of the CD4 receptor induces activation-independent down-regulation of L-selectin.

Lymphocyte circulation plays an important role in the generation of a specific immune response. Mature lymphocytes continuously circulate between blood and lymph, entering the lymphoid tissue via high endothelial venules. Trafficking across high endothelial venules of peripheral lymph nodes (PLN) depends on the expression of L-selectin. It has been shown that L-selectin is rapidly cleaved from the surface by a metalloproteinase after in vitro activation. Here, we show that ligation of CD4, without ligation of the T cell receptor for antigen, causes down-regulation of L-selectin on T helper cells. This down-regulation is caused by proteolytic cleavage by a metalloproteinase and is reversible by the addition of hydroxamic acid-based metalloproteinase inhibitors. We show that in vivo down-regulation of L-selectin in huCD4tg mice by mAb reduces the homing of lymphocytes to PLN in adoptive transfer experiments. Because CD4 is a coreceptor for HIV-1, the down-regulation of L-selectin induced by CD4 ligation could play a role in the pathogenesis of AIDS. We provide evidence that CD4 ligation by HIV-1 induces metalloproteinase-dependent L-selectin down-regulation. Reduced levels of L-selectin expression might contribute to immune deficiency in individuals infected with HIV by inhibiting T cell redistribution and decreasing the probability of an encounter between specific lymphocytes and viral antigens in PLN.

Three-dimensional segregation of supramolecular activation clusters in T cells.

Activation of T cells by antigen-presenting cells (APCs) depends on the complex integration of signals that are delivered by multiple antigen receptors. Most receptor-proximal activation events in T cells were identified using multivalent anti-receptor antibodies, eliminating the need to use the more complex APCs. As the physiological membrane-associated ligands on the APC and the activating antibodies probably trigger the same biochemical pathways, it is unknown why the antibodies, even at saturating concentrations, fail to trigger some of the physiological T-cell responses. Here we study, at the level of the single cell, the responses of T cells to native ligands. We used a digital imaging system and analysed the three-dimensional distribution of receptors and intracellular proteins that cluster at the contacts between T cells and APCs during antigen-specific interactions. Surprisingly, instead of showing uniform oligomerization, these proteins clustered into segregated three-dimensional domains within the cell contacts. The antigen-specific formation of these new, spatially segregated supramolecular activation clusters may generate appropriate physiological responses and may explain the high sensitivity of the T cells to antigen.