Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis

Curtsinger, Julie; Lins, Debra C.; Johnson, Christopher M.; Mescher, Matthew F.

doi:10.4049/jimmunol.175.7.4392

Cited by 81 publications

(61 citation statements)

References 41 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B). These results suggested that the CD107a-based degranulation assay may not precisely identify effector CD8 T cells involved in cytolysis, a finding that had been reported previously (18). Next, we questioned whether low cytotoxic activity despite normal degranulation could be explained by changes in expression level of grB, or perhaps perforin, in the cytotoxic granules of briefly stimulated OT-I cells.…”

Section: Briefly Stimulated Cd8 T Cells Show Deficiency In Cytotoxicitymentioning

confidence: 45%

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

Usharauli

Kamala

2008

The Journal of Immunology

View full text Add to dashboard Cite

It is currently believed that a brief antigenic stimulation is sufficient to induce CD8 T cells to complete their differentiation program, become effector T cells, and subsequently generate memory. Because this concept was derived from studies in which only a single effector function was analyzed (either IFN-γ production or target cell lysis), we wondered whether monitoring for multiple effector functions might reveal novel characteristics of effector CD8 T cells elicited by brief or prolonged Ag exposure. Using an in vitro system to generate effector T cells and an in vivo adoptive transfer model to track donor CD8 T cells, we found that the differentiation programs acquired by CD8 T cells after brief or prolonged antigenic stimulation were different. Although the frequencies of IFN-γ and TNF-α producers were comparable for both effector CD8 T cell populations, there were major differences in cytotoxic potential and IL-2 production. Whereas prolonged (>24 h) Ag exposure stimulated effector CD8 T cells with high cytotoxic activity and low IL-2 production, brief (<24 h) stimulation generated effector CD8 T cells with low cytotoxic activity and high IL-2 production. The latter effector T cells rapidly converted into central memory-like CD8 T cells, exhibited long-term survival in adoptively transferred hosts, and gave robust recall responses upon Ag challenge. These data suggest that not all functions of effector CD8 T cells are equally inherited after brief or prolonged antigenic stimulation.

show abstract

Section: Briefly Stimulated Cd8 T Cells Show Deficiency In Cytotoxicitymentioning

confidence: 45%

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

Usharauli

Kamala

2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Absence of lytic function may suggest partial tolerance (41). However, at least in mice, some nonlytic CD8 T cells have protective potential, for example, by IFN-␥ secretion important for CD8 T cell-mediated tumor defense (49) and protection against some viruses (50,51).…”

Section: Discussionmentioning

confidence: 99%

IL-12 Controls Cytotoxicity of a Novel Subset of Self-Antigen-Specific Human CD28+ Cytolytic T Cells

Barbey

Baumgaertner

Devêvre

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Activated CD8 T cells develop cytotoxicity against autologous cells bearing foreign Ags and self/tumor Ags. However, self-specific cytolysis needs to be kept under control to avoid overwhelming immunopathology. After peptide vaccination of melanoma patients, we studied molecular and functional properties of T cell subsets specific for the self/tumor Ag Melan-A/MART-1. Ex vivo analysis revealed three Ag-specific effector memory (EM) populations, as follows: CD28-negative EM (EM28−) T cells strongly expressing granzyme/perforin, and two EM28+ subsets, one with high and the other with low level expression of these cytotoxic proteins. For further functional characterization, we generated 117 stable CD8 T cell clones by ex vivo flow cytometry-based sorting of these subsets. All EM28−-derived clones lysed target cells with high efficacy. In contrast, EM28+-derived clones were heterogenous, and could be classified in two groups, one with high and the other with low killing capacity, correlating with granzyme/perforin expression. High and low killer phenotypes remained surprisingly stable for several months. However, strongly increased granzyme expression and cytotoxicity were observed after exposure to IL-12. Thus, the data reveal a newly identified subset of CD28+ conditional killer T cells. Because CD28 can mediate strong costimulatory signals, tight cytotoxicity control, as shown in this study through IL-12, may be particularly important for subsets of T cells expressing CD28.

show abstract

“…Perforin molecules punch holes into the membrane of the target cell and GzB penetrates inducing apoptosis via activation of caspase pathways [21][22][23]. While resting CD8 + cells (naïve and central memory cells) have no cytolytic granules containing GzB, they start expressing granzyme within days after antigen encounter -provided they also receive "signal 3" [12,23]. In the absence of ongoing antigen stimulation CD8 + cells stay GzB positive for approximately one month [24].…”

Section: Introductionmentioning

confidence: 99%

“…Naïve CD8 + cells will proliferate vigorously but will not differentiate in lytic effector cells unless they also receive a "third signal" that can be provided by IL-12 [9,10] or type I IFNs [11]. In the absence of such third signals, CD8 + cells will proliferate, express perforin but not Granzyme B (GzB) and will lack cytolytic functions [12]. If the immune response is successful and the antigen is cleared/controlled the CD8 + cells become quiescent, their clonal sizes drop, they reacquire a resting phenotype and lose the ability to engage in direct lytic effector functions.…”

Section: Introductionmentioning

confidence: 99%

Granzyme B production distinguishes recently activated CD8+ memory cells from resting memory cells

Nowacki

Küerten

Zhang³

et al. 2007

Cellular Immunology

View full text Add to dashboard Cite

For immune diagnostic purposes it would be critical to be able to distinguish between ongoing immune processes, such as active infections, and long-term immune memory, for example imprinted by infections that have been cleared a long time ago or by vaccinations. We tested the hypothesis that the secretion of Granzyme B, as detected in ex vivo ELISPOT assays, permits this distinction. We studied EBV-, flu-and CMV-specific CD8 + cells in healthy individuals, Vaccinia virus-reactive CD8 + cells in the course of vaccination, and HIV-specific CD8 + cells in HIV-infected individuals. Antigen-specific ex vivo GzB production was detected only transiently after Vaccinia immunization, and in HIV-infected individuals. Our data suggest that ex vivo ELISPOT measurements of granzyme B permit the identification of actively ongoing CD8 + cell responses -a notion that is pertinent to the immune diagnostic of infections, transplantation, allergies, autoimmune diseases, tumors, and vaccine development.

show abstract

Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis

Cited by 81 publications

References 41 publications

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

IL-12 Controls Cytotoxicity of a Novel Subset of Self-Antigen-Specific Human CD28+ Cytolytic T Cells

Granzyme B production distinguishes recently activated CD8+ memory cells from resting memory cells

Contact Info

Product

Resources

About