CTLs respond with activation and granule secretion when serving as targets for T-cell recognition.
Cytotoxic T lymphocytes (CTLs) suppress T cell responses directed against their antigens regardless of their own T cell receptor (TCR) specificity. This makes the use of CTLs promising for tolerance induction in autoimmunity and transplantation. It has been established that binding of the CTL CD8 molecule to the major histocompatibility complex (MHC) class I α3 domain of the recognizing T cell must be permitted for death of the latter cell to ensue. However, the signaling events triggered in the CTL by this molecular interaction in the absence of TCR recognition have never been clarified. Here we use single-cell imaging to study the events occurring in CTLs serving as targets for recognition by specific T cells. We demonstrate that CTLs actively respond to recognition by polarizing their cytotoxic granules to the contact area, releasing their lethal cargo, and vigorously proliferating. Using CTLs from perforin knockout (KO) mice and lymphocyte specific kinase (Lck) knockdown with specific small interfering RNA (siRNA), we show that the killing of the recognizing CD8 T cell is perforin dependent and is initiated by Lck signaling in the CTL. Collectively, these data suggest a novel mechanism in which the entire cascade generally triggered by TCR engagement is "hijacked" in CTLs serving as targets for T cell recognition without TCR ligation.
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Oren
O
Milstein
David
D
Hagin
Assaf
A
Lask
Shlomit
S
Reich-Zeliger
Elias
E
Shezen
Eran
E
Ophir
Yaki
Y
Eidelstein
Ran
R
Afik
Yaron E
YE
Antebi
Michael L
ML
Dustin
Yair
Y
Reisner
D000595:Amino Acid Sequence; D000818:Animals; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018448:Models, Immunological; D010047:Ovalbumin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
C110366:OVA-8; D010446:Peptide Fragments; D054353:Perforin; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D010047:Ovalbumin; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)