Natural amino acid polymorphisms of the circumsporozoite protein of Plasmodium falciparum abrogate specific human CD4⁺ T cell responsiveness

Abstract

Sequence polymorphism has been reported for virtually all malaria antigens and, in the case of the circumsporozoite (CS) protein, this variation is in the form of point mutations concentrated primarily in several regions recognized by T cells. The factors responsible for the variation are unknown. We studied the T cell responses to all known variants in malaria-exposed Thais. Memory CD4+ T cells responded to variants 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 variants, including the other Thai variant, and competition studies performed with the clones using analog peptides demonstrated that all the substitutions of the polymorphic residues modulate either the binding of the peptide to major histocompatibility complex (MHC) molecules or the recognition by the T cell receptor of the peptide-MHC complex. Our data suggest that CD4+ T cells may be able to select parasites expressing variant sequences and have implications for development of a CS-based vaccine.

The London School of Hygiene and Tropical Medicine: a new century of malaria research

“…The role of allelic variation in genes encoding immunodominant antigens of the parasite is hotly debated but it seems clear that antigenic polymorphism can lead to immune evasion. The data are most convincing for evasion of cell-mediated immunitypolymorphisms cluster around immunodominant T cell epitopes (Good et al 1988), single amino acid substitutions in T cell epitopes lead to loss of T cell recognition (Zevering et al 1994) or antagonism of T cell responses (Plebanski et al 1999) and nonsynonymous mutations out-number synonymous mutations within T cell epitopes (Hughes et al 1995). Polymorphisms that allow the parasite to evade host immune responses will tend to be maintained by frequency dependent (or balancing) selectioni.e.…”

Genetic Diversity and Antigenic Polymorphism in Plasmodium falciparum : Extensive Serological Cross-Reactivity between Allelic Variants of Merozoite Surface Protein 2

“…In some genes (e.g., the circumsporozoite surface protein [csp] gene), point mutations cluster in areas immunodominant for T cells (16) and can lead to loss of epitope recognition (38) or antagonism of T-cell responses (26), although it is not clear that either of these leads to the avoidance of protective immunity. Similarly, monospecific antibodies differentiate between allelic variants of merozoite surface proteins (13,23), but the human antibody response is commonly directed at conserved or semiconserved epitopes (8,34) and direct evidence for the evasion of antibody-dependent immunity is lacking.…”

Population structure and recent evolution of Plasmodium falciparum

“…Numerous studies have indicated that Csp, Msp-1, Msp-2, and other antigenic genes are polymorphic and that their multiple allelic forms differ in their ability to abrogate recognition by the host's immune response (3)(4)(5)(6)(7). These observations have been interpreted as instantiation of widespread polymorphism throughout the genome.…”