Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control

Stephen A. Migueles, Christine M. Osborne, Cassandra Royce, Alex A. Compton, Rohan P. Joshi, Kristin A. Weeks, Julia E. Rood, Amy M. Berkley, Jonah B. Sacha, Nancy A. Cogliano-Shutta, Margaret Lloyd, Gregg Roby, Richard Kwan, Mary McLaughlin, Sara Stallings, Catherine Rehm, Marie A. O'Shea, Jo Ann Mican, Beverly Z. Packard, Akira KomoriyaSarah Palmer, Ann P. Wiegand, Frank Maldarelli, John M. Coffin, John W. Mellors, Claire W. Hallahan, Dean A. Follman, Mark Connors

Research output: Contribution to journalArticle

352 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1009-1021
Number of pages13
JournalImmunity
Volume29
Issue number6
DOIs
StatePublished - Dec 19 2008

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Keywords

  • CELLIMMUNO
  • HUMDISEASE

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Migueles, S. A., Osborne, C. M., Royce, C., Compton, A. A., Joshi, R. P., Weeks, K. A., Rood, J. E., Berkley, A. M., Sacha, J. B., Cogliano-Shutta, N. A., Lloyd, M., Roby, G., Kwan, R., McLaughlin, M., Stallings, S., Rehm, C., O'Shea, M. A., Mican, J. A., Packard, B. Z., ... Connors, M. (2008). Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control. Immunity, 29(6), 1009-1021. https://doi.org/10.1016/j.immuni.2008.10.010