A synaptic basis for T-lymphocyte activation

Abstract

T lymphocytes respond to foreign antigen by forming specialized junctions with antigen-presenting cells (APC) or target cells. A hypothesis is presented, illustrating the similarity between the T-cell recognition-activation process and the cell communication processes found in other organ systems, especially the nervous system. Based on data showing that a major neuronal protein, Thy-1, is also a mitogenic site on T cells, and based on predictions for the structures of the T-cell receptor (TcR) and Ia proteins, an activation model is presented as follows. 1) The T-cell receptor initiates cell-cell contact with the APC by interacting with Ia and antigen, forming an antigen-binding site. 2) Sets of adhesion molecules then bind, focusing the interacting proteins to the junctional site. One binding protein, L3/T4, binds Ia and concentrates the Ia molecules to the contact site. 3) The two-chain TcR then links together the TcR-Ia-antigen complexes, forming a linear chain of receptors which will self-associate once reaching a critical length, forming a cluster. This cluster juxtaposes associated channel subunits, the T3 membrane molecules, creating an ion channel, stimulating the T cell. 4) The MHC molecule is structurally a part of this activation complex, and therefore also forms a cluster on the APC surface, possibly activating the presenting cell. 5) Secretory products are then released into the synaptic site allowing for efficient and directed cell-cell communication. Cytolytic class-I-restricted cells use a similar pathway to focus the effect of cytolytic proteins. This analogy views neuronal communication and lymphoid recognition as evolutionary descendents of a primordial lymphocytic type of cell interaction.

Fig. 1. The T-cell antigen/MHC receptor complex and class II molecules

The oval structures represent Ig-like domains and the abbreviations are as follows. For the T-cell receptor shown on the T-cell membrane (above): Tvβ = β-chain variable region; Tcβ = β-chain constant region; Tvα = α-chain variable region; Tcα = α-chain constant region; T3 = 20 kDa glycosylated T3 peripheral protein: Thy – Thy-1 or T3 25-28 kDa molecule; T3m = T3 membrane component. For the Ia molecules: β1 = β-chain polymorphic first domain; β2 = β-chain membrane proximal domain; α1 = α-chain first domain; α2 = α-chain second domain; Ia-Id = Ia idiotype. The thickened areas represent polymorphic regions in the domain. The antigen fragment depicts the proposed α-helical cylochrome c fragment [50] with carboxy terminal positively charged lysine residues interacting with the recognition unit.

Fig. 2. T-cell activation complexes; ion channel formation

The complexes are viewed from above with the plane of the paper in the plane of the membrane. β and α represent the first domains of the Ia molecules. TcR.Vβ and Vα are the two variable regions. The Thy-1 molecule (T1) is attached to the TcR constant region via the T3(20 kDa) molecule (not shown) and to the T3 membrane component labelled as T3. The linear chain will self-associate to form a ring juxtaposing the T3 membrane proteins forming the ion channel.

Fig. 3. The T-cell synaptic-junctional complex

The sequence of binding events is described in the text. LFA-1 is shown binding to another LFA-like molecule on the APC which is not specifically LFA-1.