GENERATION AND MAINTENANCE OF MEMORY T CELL RESPONSES DURING PERSISTENT EHRLICHIAL INFECTION AND THE ROLE OF CD4+CD25+FOXP3+ T REGULATORY CELLS IN EHRLICHIAL PERSISTENCE

Nagaraja Thirumalapura¹, Emily Crossley¹, David H. Walker, M.D.¹ and Nahed Ismail, M.D., Ph.D.²

¹Department of Pathology, UTMB, ²Meharry Medical College, Nashville, TN

Background: Human monocytotropic ehrlichiosis (HME), an emerging and often life-threatening tick-transmitted disease in the United States, is caused by the obligately intracellular bacterium Ehrlichia chaffeensis. Currently, no vaccine is available against HME. Objective: The objectives of the present study were to investigate the maintenance of memory T cells responses in the presence and absence of persistent ehrlichial infection and to understand the role of CD4+CD25+Foxp3+ T regulatory cells in persistence of ehrlichial infections. Methods: We examined the memory T cell responses maintained in the presence and absence of persistent Ehrlichia muris infection in C57BL/6 mice by termination of persistent infection with antibiotic treatment after the development of adaptive immunity. Results: The study indicated that (1) memory T cells maintained in the presence of persistent E. muris infection did not appear to enter a state of dysfunction or exhaustion, (ii) the magnitude of memory T cell responses, but not the quality of memory T cells, was compromised in the absence of persistent infection, which corresponded to lower levels of protection against an ordinarily lethal dose of heterologous infection with Ixodes ovatus Ehrlichia in the absence of persistent E. muris infection, and (iii) CD4+CD25+Foxp3+ T regulatory cells expand during persistent E. muris infection; however, depletion of CD25+ T cells did not alter either T cell responses against Ehrlichia or the bacterial burden. Conclusions: (i) Persistent ehrlichial infection contributed to heterologous protection by stimulating maintenance of memory T cell responses and (ii) CD4+CD25+Foxp3+ T regulatory cells had a minimal demonstrated role in persistence of ehrlichial infection. Supported by the McLaughlin Endowment and NIAID RO1 AI 31431.