Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control.
Virus-specific CD8+ T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIV-specific CD8+ T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.
Migueles
Stephen A
SA
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Osborne
Christine M
CM
Royce
Cassandra
C
Compton
Alex A
AA
Joshi
Rohan P
RP
Weeks
Kristin A
KA
Rood
Julia E
JE
Berkley
Amy M
AM
Sacha
Jonah B
JB
Cogliano-Shutta
Nancy A
NA
Lloyd
Margaret
M
Roby
Gregg
G
Kwan
Richard
R
McLaughlin
Mary
M
Stallings
Sara
S
Rehm
Catherine
C
O'Shea
Marie A
MA
Mican
JoAnn
J
Packard
Beverly Z
BZ
Komoriya
Akira
A
Palmer
Sarah
S
Wiegand
Ann P
AP
Maldarelli
Frank
F
Coffin
John M
JM
Mellors
John W
JW
Hallahan
Claire W
CW
Follman
Dean A
DA
Connors
Mark
M
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D015550:Cell Degranulation / Q000276:immunology; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology
D012367:RNA, Viral; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes