Antigen recognition by T cells Zheng W. Chen, M.D., Ph.D

T cell receptors (TCR) on T cells recognize antigens TCR is a heterodimer comprised of 2 transmembrane glycoprotein chains; TCR  chain and TCR  chain.  TCR heterodimers are very similar in structure to a Fab fragment of immunoglobulin, bearing V, (D), J, C segments. A majority of T cells express  TCR heterodimers; a minority of T cells express another type of TCR,  TCR heterodimers. CDR loops of TCR form the antigen- binding sites. Theoretically, each T cell expresses a unique TCR in terms of VDJ sequences.

T cell receptor  heterodimers

TCR CDR loops form the antigen-binding sites

TCR recognize antigen peptide presented by a MHC molecule l TCR recognition of antigen differs from antibody recognition of antigen (TCR cannot bind directly to an antigen peptide). l Ag peptide must be presented by a corresponding MHC molecule before TCR can recognize. l TCR interact with the peptide-MHC complex (ligand) by making contact with both the antigen peptide and the MHC (“Dual recognition”).

Class I is comprised of one transmembrane glycoprotein (  chain) and a  2- microglobulin; Class II are dimmers of   and  transmembrane glycoproteins

CD4 T cell recognize antigen peptides bound to MHC class II molecules; CD8 T cells recognize antigen peptides bound to MHC class I molecules. Historically, T cell (TCR) recognition of antigen peptides were characterized by antigen peptide stimulation assays in culture: CD4 T cells + specific Ag peptide Interleukin 2 (IL-2) APC or Interferon  (IFN-  ) CD8 T cells + specific Ag peptide cytotoxic killing of target cells (target cells) APC or production of IFN- 

Why CD4 T cells recognize peptide/MHC class II and CD8 T cells see peptide/MHC class I ? CD4 + T cells CD8 + T cells

Antigen presenting cells (APC) and expression of MHC class I and II molecules Professional APC: macraphages/monocytes/Langerhams cells; dendritic cells, B cells, express both MHC class II and I. In general, all tissue cells can express Class I; but not Class II (endothelial cells can express both).

Class I molecules bind short peptides of 8-10 amino acids by both ends (binding sites for anchor residues of a given peptide).

MHC Class II molecules bind AA or longer peptides

TCR binds to the MHC:peptide complex

New studies from my lab and others have shown that human and higher primate  T cells can recognize nonpeptide phosphoantigen from mycobacteria (shen et al, Science 2002)  TCR ??? presenting cells Ag presentation  TCR peptide MHC APC phosphoAg ???  T cells  T cells

Phosphoantigen-specific  T cells expressing V  2V  2 TCR can undergo major clonal expansion in mycobacterial infection. (Shen et al, Science; Chen et al, Trends Immunol, 2003).