Increased sensitivity of CD4+ T-effector cells to CD4+CD25+ Treg suppression compensates for reduced Treg number in asymptomatic HIV-1 infection.
BACKGROUND
In HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg) numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue.


RESULTS
A classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25- effectors cells (E) following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27) and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14). HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047). Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25- effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV.


CONCLUSIONS
Together, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection.
Thorborn
Georgina
G
Department of Infectious Diseases, King's College London, Guys' Hospital, London, England.
Pomeroy
Laura
L
Isohanni
Heidi
H
Perry
Melissa
M
Peters
Barry
B
Vyakarnam
Annapurna
A
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology
D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens