'Natural' T cells responsive to malaria: Evidence implicating immunological cross-reactivity in the maintenance of TCRαβ⁺ malaria-specific responses from non-exposed donors

It is now generally accepted that peripheral blood of humans not exposed previously to malaria contains T cells which proliferate vigorously in response to malaria parasites and antigens. Although it has been claimed that these cells express a memory phenotype, their origin is uncertain. We have examined the phenotype and immunological responses of such cells. We confirm that these cells do express the 'memory phenotype', CD45Ro, in that depletion of such cells, but not of CD45Ra (virgin) cells, abrogates the immune response to malaria parasites. In an effort to define the genesis of these responses, numerous malaria-specific T cell clones have been generated from non-exposed individuals. These were tested for reactivity to a large panel of common bacterial, viral, and fungal pathogenic and non-pathogenic organisms. Most clones proliferated vigorously in response to one or more such organisms, while many clones demonstrated smaller but significant degrees of proliferation in response to many different organisms. Our data offers insights into the maintenance of immunological memory. All clones examined were CD3 ⁺, CD4 ⁺, CD8^-, TCRαβ⁺, and TCRδ^-. The ratio of TCRαβ⁺ to TCRδ⁺ cells among peripheral blood lymphocytes increased during polyclonal culture in the presence of parasite. The high frequency of such cells in peripheral blood (1/800-1/9000), and their response to a wide range of geographically different Plasmodium falciparum isolates and clones by both proliferation and lymphokine secretion (predominantly IFN-γ) with a high degree of sensitivity (<1 parasite/μI blood in some cases) suggests that these cells must be quickly activated following malaria infection. Their contribution to the outcome of the disease protection/immunopathology) may be significant.