Kaj Saizawa

CD4+ T Cells: Specificity and Function

The majority of T lymphocytes, and those best-characterized at the present time, recognize foreign antigens as peptide fragments associated with self major histocompalibility complex (MHC)-encoded proteins. The reason for this preoccupation of T cells with MHC-encoded cell surface molecules is not presently understood, and controversy surrounds many aspects of MHC restriction in T cell specificity. Both T cells and MHC molecules can be subdivided into two classes. MHC class I molecules are found on the surface of most somatic cells, while MHC class II molecules are expressed selectively on the surfaces of cells involved in immune responses, such as B cells and macrophages. T cells can be subdivided by the cell surface expression of the CD4 and CD8 markers: CD4 T cells recognize foreign protein antigen fragments associated with self class II MHC molecules, while CDS T cells recognize foreign protein antigen fragments associated with self class I MHC molecules. T cells also respond to polymorphic differences in MHC molecules. Recognition of allogeneic or non-self MHC molecules largely follows the pattern of foreign antigen recognition, with CD4 T cells predominantly recognizing class II MHC polymorphisms, and CD8 T cells largely recognizing class I MHC polymorphisms. These responses to non-self MHC molecules involve a very high proportion of normal T cells, it being estimated that 1-10% of T cells will respond to a particular non-self MHC molecule. This surprising commitment of T cells to recognition of MHC molecules not normally encountered requires a biologically satisfying explanation. These fmdings raise several questions: First, why is expression of CD4 associated with recognition of foreign antigen in association with self class II MHC molecules? Second, how can one account for the high frequency of alloreactive T cells? And third, why

The co-receptor function of murine CD4.

Peripheral T cells can be subdivided into two major sets based on the differential expression of the cell surface molecules CD4 and CD8. It was noted early that the CD4 T-cell subset recognized antigen presented by class II MHC molecules, while the CD8 subset recognized antigen presented by class 1 MHC molecules (Swain 1983). We will term this phenomenon the specificity association; the association of CD4 expression with class II MHC restricted antigen recognition is fare more absolute than is the association with helper function (Janeway et al. 1988). The observed specificity association has led to two suggestions: First, that CD4 and CD8 bind to non-polymorphic portions of class II and class I MHC molecules, respectively, and second, that CD4 and CD8 are accessory molecules whose major function is to augment the interaction of T cells with antigenpresenting cells bearing tbe appropriate MHC molecule (Dialynas et al. 1983). In this review, data will be presented that supports the alternative view that the major function of CD4 is in forming a part of the T-cell receptor for its complex class II MHC ligand (Saizawa et al. 1987a, Janeway et al. 1988, Janeway 1989). By inference, CD8 would serve a similar role in class I MHC recognition. Because our data point of CD4 as a physical component of the T-cell receptor (TCR) for antigenic peptides bound to class II MHC molecules, we believe that the term co-receptor (Janeway 1988) more accurately reflects the role of this molecule in T-cell activation and specificity than does the term accessory molecule,

Recognition of MHC Class II Antigens by the CD4: T Cell Receptor Complex

T lymphocytes that express CD4 respond to foreign antigens presented in the context of syngeneic class II MHC molecules. T cells responding to allogeneic class II MHC molecules generally express CD4, but exceptions are observed. We show that the same receptor on a cloned T cell line recognizes both foreign antigen associated with self-class II MHC and nonself-class II MHC molecules. The role of CD4 in these recognition responses appears to be to bind to class II MHC molecules and, through association with the T cell receptor recognizing the same class II MHC molecule, to effectively activate the T cell. It is proposed on the basis of these two findings that the high ligand multiplicity of alloantigens recognized in unmodified form by high affinity anti-nonself-MHC receptors can explain the finding of CD8+ T cells responding to nonself-class II MHC molecules, as well as the inability of anti—CD4 to inhibit such nonself-class II MHC recognition completely. Finally, data will be presented to suggest that class II may also play a role in selecting the functional activity elicited in response to a protein antigen in vivo. These data show that the CD4:T cell receptor complex interaction with the complex of foreign antigen and self-MHC is the critical event in initiating most immune responses and may also play a role in controlling their functional outcome.