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Soluble MHC-Peptide Complexes Induce Rapid Death of CD8⁺ CTL¹

Marek Cebecauer^*, Philippe Guillaume^*, Pavel Hozák, Silke Mark^*, Helen Everett, Pascal Schneider and Immanuel F. Luescher^2,*

^* Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; and Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Soluble MHC-peptide (pMHC) complexes, commonly referred to as tetramers, are widely used to enumerate and to isolate Ag-specific CD8⁺ CTL. It has been noted that such complexes, as well as microsphere- or cell-associated pMHC molecules compromise the functional integrity of CTL, e.g., by inducing apoptosis of CTL, which limits their usefulness for T cell sorting or cloning. By testing well-defined soluble pMHC complexes containing linkers of different length and valence, we find that complexes comprising short linkers (i.e., short pMHC-pMHC distances), but not those containing long linkers, induce rapid death of CTL. This cell death relies on CTL activation, the coreceptor CD8 and cytoskeleton integrity, but is not dependent on death receptors (i.e., Fas, TNFR1, and TRAILR2) or caspases. Within minutes of CTL exposure to pMHC complexes, reactive oxygen species emerged and mitochondrial membrane depolarized, which is reminiscent of caspase-independent T cell death. The morphological changes induced during this rapid CTL death are characteristic of programmed necrosis and not apoptosis. Thus, soluble pMHC complexes containing long linkers are recommended to prevent T cell death, whereas those containing short linkers can be used to eliminate Ag-specific CTL.

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