Blood Journal
Leading the way in experimental and clinical research in hematology

Paucity of interleukin (IL-21)-producing CD4+ T-cells is associated with Th17 cell depletion in SIV-infection of rhesus macaques

  1. Luca Micci1,
  2. Barbara Cervasi1,
  3. Zachary S. Ende1,
  4. Robin I. Iriele1,
  5. Elane Reyes-Aviles2,
  6. Carol Vinton3,
  7. James Else1,
  8. Guido Silvestri1,
  9. Aftab A. Ansari4,
  10. Francois Villinger5,
  11. Savita Pahwa6,
  12. Jacob D. Estes7,
  13. Jason M. Brenchley3, and
  14. Mirko Paiardini1,*
  1. 1 Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States;
  2. 2 Case Western University, Cleveland, OH, United States;
  3. 3 Program in Barrier Immunity and Repair and Lab of Molecular Microbiology, NIAID, NIH, Bethesda, MD, United States;
  4. 4 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States;
  5. 5 Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States;
  6. 6 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States;
  7. 7 AIDS Cancer Virus Program, NCI-Frederick, Frederick, MD, United States
  1. * Corresponding author; email: mirko.paiardini{at}


Interleukin (IL)-21 regulates Th17 cell homeostasis, enhances the differentiation of memory B cells and antibody-secreting plasma cells, and promotes the maintenance of CD8+ T-cell responses. In this study, we investigated the phenotype, function, and frequency of blood and intestinal IL-21-producing cells in nonhuman primates that are hosts of progressive (rhesus macaques; RMs) and nonprogressive (sooty mangabeys; SMs) SIV infection. We found that, in both species, memory CD4+CD95+CCR6- T-cells are the main IL-21 producers, and that only a small fraction of CD4+IL-21+ T-cells produce IL-17. During chronic SIV infection of RMs, CD4+IL-21+ T-cells were significantly depleted in both blood and rectal mucosa, with the extent of this depletion correlating with the loss of Th17 cells. Furthermore, treatment with IL-21 increased the in vivo levels of Th17 cells in SIV-infected RMs. In contrast, normal levels of CD4+IL-21+ T-cells were found in SIV-infected SMs. Collectively, these data indicate that depletion of IL-21-producing CD4+ T-cells distinguishes progressive from nonprogressive SIV infection of RMs and SMs, and suggest that depletion of CD4+IL-21+ T-cells is involved in the preferential loss of Th17 cells that is associated with SIV disease progression. Further pre-clinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.

  • Submitted April 2, 2012.
  • Accepted August 31, 2012.