Identification of T cell antigens in the 21st century, as difficult as ever

Identifying antigens recognized by T cells is still challenging, particularly for innate like T cells that do not recognize peptides but small metabolites or lipids in the context of MHC-like molecules or see non-MHC restricted antigens. The fundamental reason for this situation is the low affinity of T cell receptors for their ligands coupled with a level of degeneracy that makes them bind to similar surfaces on antigen presenting cells. Herein we will describe non-exhaustively some of the methods that were used to identify peptide antigens and briefly mention the high throughput methods more recently proposed for that purpose. We will then present how the molecules recognized by innate like T cells (NKT, MAIT and γδ T cells) were discovered. We will show that serendipity was instrumental in many cases.