Annual Review of Immunology - Volume 13, 1995

The ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors.

Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.

Over the past decade, a variety of ion channels have been identified and characterized in lymphocytes by use of the patch-clamp technique. This review discusses biophysical and regulatory aspects of lymphocyte potassium and calcium channels with the aim of understanding the role of these channels in lymphocyte functions. Lymphocytes express both voltage-dependent potassium [K(V)] channels and calcium-activated potassium [K(Ca)] channels, and each is upregulated as cells progress toward division following mitogenic stimulation. The genes encoding two K(V) channels, Kv1.3 (type n) and Kv3.1 (type l), have cloned. Mutational analysis is revealing functionally important regions of these channel proteins. Exogenous expression studies and the use of highly specific channel blockers have helped to establish the roles of type n K(V) channels sustaining the resting membrane potential, in regulating cell volume, and in enabling lymphocyte activation. Blockade of K(V) and K(Ca) channels effectively inhibits the antigen-driven activation of lymphocytes, probably by inducing membraned epolarization and thereby diminishing calcium influx. A prolonged rise in intracellular calcium ([ Ca²⁺]i) is a required signal for lymphocyte activation by antigen or mitogens. Single-cell fluorescence measurements have revealed underlying [Ca²⁺]i oscillations that are linked closely to the opening and closing of Ca²⁺ and K⁺ channels. Sustained Ca²⁺ signaling and oscillations depend absolutely on plasma-membrane Ca²⁺ channels that are activated by the depletion of intracellular calcium stores. Under physiological conditions these channels open as a consequence of store depletion induced by inositol 1,4,5-trisphosphate (IP3), but they can also be activated experimentally by several agents that empty the stores without generating IP3, such as the microsomal Ca²⁺-ATPase inhibitor thapsigargin. The intricate causal relationships among ion channels, membrane potential, [Ca²⁺]i, and lymphokine gene expression can now be pursued at the single-cell level with patch-clamp recording, calcium-dependent dyes, reporter genes, and fluorescence video techniques. These approaches will help to clarify the essential roles of ion channels in the molecular pathways subserving activation and other lymphocyte behaviors.

In this review we have attemped to define the characteristics of TI-2 antigens that enable them to stimulate antibody production in the absence of T cell help. One of the most critical properties of this group of antigens is their ability to deliver prolonged and persistent signaling to the B cell. This by itself is not however sufficient to stimulate Ig synthesis, and they mus therefore stimulate non-T cells to interact with the B cells either directly or indirectly via cytokine production. There is evidence implicating the NK cell and T cell as playing this important role in response to TI antigens. Furthermore, we discuss the importance of cytokines such as IL-3, GMCSF and IFN-γ, which significantly enhance antibody production by these antigens. Finally, we present evidence demonstrating that B cell activation via TI stimuli does not play merely a permissive role in allowing for cell cycle entry and enhanced responsiveness to other stimuli. Rather, the nature of the B cell activating signal is critical in determining the quantitative and qualitative profile of Ig isotype production.