NATURAL AMINO-ACID POLYMORPHISMS OF THE CIRCUMSPOROZOITE PROTEIN OF PLASMODIUM-FALCIPARUM ABROGATE SPECIFIC HUMAN CD4(-CELL RESPONSIVENESS() T)

Sequence polymorphism has been reported for virtually all malaria anti gens and, in the case of the circumsporozoite (CS) protein, this varia tion is in the form of point mutations concentrated primarily in sever al regions recognized by T cells. The factors responsible for the vari ation are unknown. We studied the T cell responses to all known varian ts in malaria-exposed Thais. Memory CD4(+) T cells responded to varian ts of a polymorphic immunodominant region (denoted Th2R), and CD4(+) T cell clones specific for one Thai Th2R variant were generated. There was minimal cross-reactivity to any of the naturally occurring variant s, including the other Thai variant. and competition studies performed with the clones using analog peptides demonstrated that all the subst itutions of the polymorphic residues modulate either the binding of th e peptide to major histocompatibility complex (MHC) molecules or the r ecognition by the T cell receptor of the peptide-MHC complex. Our data suggest that CD4(+) T cells may be able to select parasites expressin g variant sequences and have implications for development of a CS-base d vaccine.