Highly conserved regions of the immunodominant major surface protein 2 of the genogroup II ehrlichial pathogen Anaplasma marginale are rich in naturally derived CD4(+) T lymphocyte epitopes that elicit strong recall responses

Genogroup II ehrlichia, including the agent of human granulocytic ehrlichio sis, Ehrlichia phagocytophila, and the bovine pathogen Anaplasma marginale, express a markedly immunodominant outer membrane protein designated major surface protein 2 (MSP2). MSP2 is encoded by a multigene family, resulting in the expression of variant B cell epitopes. MSP2 variants are sequentiall y expressed in the repeated cycles of rickettsemia that characterize persis tent A. marginale infection and control of each rickettsemic cycle is assoc iated with development of a variant-specific IgG response. Importantly, the se persistent rickettsemic cycles are controlled at levels 100-1000 times l ower than those responsible for clinical disease during acute infection. Co ntrol of rickettsemia during persistence could result from an anamnestic Th lymphocyte response to conserved regions of MSP2 that enhances the primary Ab response against newly emergent variants. Comparison of MSP2 variants r eveals conserved N and C termini Banking the central, surface-exposed hyper variable region that represents the variant B lymphocyte epitopes. We demon strate MSP2-specific CD4(+) T lymphocyte recognition of epitopes common to several strains of A, marginale and the related pathogen A. ovis. Furthermo re, T lymphocyte lines from three individuals identified six to nine overla pping peptides representing a minimum of four to seven dominant or subdomin ant epitopes in these conserved N and C termini, Immunodominant peptides in duced high levels of IFN-gamma, a cytokine associated with protection again st ehrlichia and needed for rapid generation of variant-specific IgG2. The presented data support the potential importance of a strong Th lymphocyte r esponse to invariant MSP2 epitopes in controlling rickettsemia during persi stent infection to subclinical levels.