In Vitro Human Memory CD8 T Cell Expansion in Response to Cytomegalovirus Requires CD4+T Cell Help

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Abstract
Requirements for human memory CD8+ T cell expansion are incompletely understood. We found that human cytomegalovirus (HCMV) induced expansion of memory CD8+ T cells in vitro without requiring intracellular viral peptide synthesis. Peptide-major histocompatibility complex class I tetramer binding confirmedexpansion of cells with HCMV-peptide specificity. Expansion of memory CD8+ T cells was completely dependent on the presence and function of CD4+ T cells, whose “help” also could be induced by exposure to irrelevant antigen. Recombinant interleukin (IL)-2 or IL-15 could substitute for help provided by CD4+ T cells, whereas CD8+ T cell expansion was blocked by anti-IL-2 but not anti-IL-15 antibody. Human memory CD8+ T cells expand dramatically in vitro in response to cross-presentation of HCMV antigens, and, in contrast to observations made in murine systems, this proliferation was critically dependent on CD4+ T cells that provide essential IL- 2. Thus, in humans, cross-presentation and expansion of memory CD8+ T cells may be compromised in disease states that result in deficits in CD4+ T cell numbers or function, such as may be seen in human immunodeficiency virus type 1 infection.

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