CD8 + T cells promote tubule-interstitial damage in malariainduced acute kidney injury

Douglas Esteves Teixeira¹Sarah Aparecida dos Santos Alves¹Alessandro Sá Pinheiro²Leandro Souza Silva³Rodrigo Pacheco Silva-Aguiar¹Diogo Barros Peruchetti⁴Tatiana Almeida Pádua⁵Mariana Conceição de Souza⁵Celso Caruso-Neves¹Ana Acacia Sá Pinheiro^6*

• ¹Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Paraná, Brazil
• ²Case Western Reserve University, Cleveland, Ohio, United States
• ³Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
• ⁴Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
• ⁵Farmanguinhos, Fiocruz, Rio de Janeiro, Paraná, Brazil
• ⁶Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Malaria acute kidney injury (MAKI) is associated with severe malaria and correlates with poor prognosis and death of patients infected with Plasmodium falciparum. The pathogenesis of MAKI is not completely understood but some hypotheses are well recognized. Host-parasite interactions lead to mechanical obstruction, disorders in the renal microcirculation, and immune-mediated glomerular injury. In the present work, we investigated the influence of CD8 + T cells in the pathogenesis of malaria-induced renal disease. Using C57BL/6 mice infected with Plasmodium berghei ANKA as a model of severe malaria, we observed that treatment of infected mice with FTY720, an immunomodulator that sequesters T cells in lymphoid organs and reduces their migration, prevented the development of proteinuria and an increase in the urine to creatinine ratio. Moreover, FTY720 reduced the levels of urinary -glutamyl transferase (-GT), a marker of renal tubular injury, but did not change plasma urea and creatinine, 2 different markers of glomerular function. Adoptive transfer of total T cells from malaria-infected mice to naive acceptor mice reproduced the kidney tubule-interstitial damage with no effect on glomerular function. The specific depletion of CD8 + T cells selectively protected the mice from tubular injury, but the development of glomerular damage was still observed. Our results add new knowledge demonstrating that CD8 + T cells have a specific role in tubule-interstitial injury pathology during MAKI 1.