Plasmodium falciparum-specific T cell clones from non-exposed and exposed donors are highly diverse in TCR beta chain...

Humans lacking previous exposure to Plasmodium falciparum typically have a high frequency of malaria-reactive T cells in peripheral blood, which cross-react with antigens from other microorganisms. We studied a large number of malaria-specific human T cell clones from non-exposed and malaria-exposed donors to determine whether this response is oligoclonal, and might therefore be generated by a limited number of cross-reactive epitopes. Most clones responded well to schizont antigen from three antigenically distinct stocks of P. falciparum. Clones derived from the same donor tended to show similar patterns of reactivity to a panel of non-malaria antigens from various microorganisms, suggesting that a limited number of epitopes were recognized by individuals. However, analysis of the usage of V segments of the beta chain of the TCR (TCRBV) revealed no evidence of TCRBV restriction in the T cell response, either within individual donors or across all donors. An apparent skewing towards TCRBV8 in one donor was shown by two methods to be due to in vitro expansion of a single clone: (i) Direct sorting of TCRBV8+ CD4+ T cells from fresh PBMC did not reveal any enrichment for pRBC-reactive cells; (ii) Sequencing of VDJ regions revealed that the TCRBV8 clones were identical. Sequences of non-TCRBV8 clones from this donor showed major differences in the VDJ junctional region. No differences in TCRBV repertoire between non-exposed and exposed donors were observed. These results exclude the existence of a malarial superantigen and suggest that the T cell response to malaria schizont antigen in non-exposed donors is driven by a large number of epitopes.