IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates.
HIV infection selectively targets CD4+ effector memory T (T EM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the T EM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ T EM cells with little effect on the naive or central memory T (T CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ T EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4 + T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.
Picker
Louis J
LJ
Vaccine and Gene Therapy Institute, Department of Pathology, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA. pickerl@ohsu.edu
Reed-Inderbitzin
Edward F
EF
Hagen
Shoko I
SI
Edgar
John B
JB
Hansen
Scott G
SG
Legasse
Alfred
A
Planer
Shannon
S
Piatak
Michael
M
Lifson
Jeffrey D
JD
Maino
Vernon C
VC
Axthelm
Michael K
MK
Villinger
Francois
F
D000818:Animals; D044966:Anti-Retroviral Agents / Q000276:immunology / Q000627:therapeutic use; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000276:immunology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D008297:Male; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019562:Viral Load; D014779:Virus Replication
D044966:Anti-Retroviral Agents; C515370:CCR7 protein, human; D018106:CD28 Antigens; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D054400:Receptors, CCR7; D019707:Receptors, Chemokine