Nephritogenic T cells use granzyme C as a cytotoxic mediator

Bailey, Naila Celesta; Kelly, Carolyn

doi:10.1002/eji.1830270926

Cited by 19 publications

(12 citation statements)

References 46 publications

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“…Although granzyme expression could only be assessed at the mRNA level because of lack of reagents for protein detection, the data presented here suggest a substantial effect of IL-4 on the expression of three of these proteases, granzymes A, B, and C. This effect was most profound for granzyme C. Perforin is known to play a crucial role in the granule exocytic pathway of cytotoxicity (36,44,45), whereas granzyme B contributes to the rapid apoptotic death detected in 51 Cr release assays (46,47) and granzyme A has been proposed to act independently of granzyme B (48). The function of granzyme C, however, is enigmatic, and only one report has attributed any role to this mediator in lymphocyte cytotoxicity (49). For the moment, the significance of its inhibition by IL-4 is obscure.…”

Section: Discussionmentioning

confidence: 99%

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

Kienzle

Buttigieg

Groves

et al. 2002

The Journal of Immunology

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Immune deviation of cytolytic T cell function, induced by type 2 cytokines like IL-4, is an attractive concept to explain failure of the immune system in some diseases. However, this concept is challenged by previous conflicting results on whether type 2 cytokine-producing CD8+ T cells are cytolytic. Therefore, we have analyzed the relationship between cytolytic activity and cytokine production among large numbers of primary CD8+ T cell clones. Single murine CD8+ T cells of naive phenotype were activated at high efficiency with immobilized Abs to CD3, CD8, and CD11a in the presence of IL-2 (neutral conditions) or IL-2, IL-4, and anti-IFN-γ Ab (type 2-polarizing conditions) for 8–9 days. Under neutral conditions, most clones produced IFN-γ without IL-4 and were cytolytic. Under type 2-polarizing conditions, most clones produced IFN-γ and IL-4 but displayed variable cytolytic activity and CD8 expression. Separation on the basis of surface CD8 levels revealed that, compared with CD8high cells from the same cultures, CD8low cells were poorly cytolytic and expressed low levels of perforin mRNA and protein and granzyme A, B, and C mRNA. A similar, smaller population of noncytolytic CD8low cells was identified among CD8+ T cells activated in mixed lymphocyte reaction with IL-4. Variable efficiency of generation of the noncytolytic cells may account for the differing results of earlier studies. We conclude that IL-4 promotes the development of a noncytolytic CD8low T cell phenotype that might be important in tumor- or pathogen-induced immune deviation.

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Section: Discussionmentioning

confidence: 99%

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

Kienzle

Buttigieg

Groves

et al. 2002

The Journal of Immunology

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“…Recent data suggest that the relative contributions of granzymes A and B depend on properties of the target cell (14). The function of granzyme C is unknown, although a role in cytotoxicity of a T cell clone has been reported (15).…”

Section: D8mentioning

confidence: 99%

Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8⁺T cells in influenza virus-infected mice

Johnson

Costelloe

FitzPatrick

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

138

114

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“…Here, we describe the crystal structure of granzyme C (gzmC), a rodent S1 serine protease expressed by cells of the immune system, which has been proposed to induce apoptosis in target cells (5,6). However, gzmC cannot cleave a range of peptide substrates (7) and cannot bind diisopropyl fluorophosphate, indicating that the active site is distorted or highly constrained (8).…”

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confidence: 99%

Structure of granzyme C reveals an unusual mechanism of protease autoinhibition

Kaiserman¹,

Buckle²,

Damme

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Proteases act in important homeostatic pathways and are tightly regulated. Here, we report an unusual structural mechanism of regulation observed by the 2.5-Å X-ray crystal structure of the serine protease, granzyme C. Although the active-site triad residues adopt canonical conformations, the oxyanion hole is improperly formed, and access to the primary specificity (S1) pocket is blocked through a reversible rearrangement involving Phe-191. Specifically, a register shift in the 190-strand preceding the activesite serine leads to Phe-191 filling the S1 pocket. Mutation of a unique Glu-Glu motif at positions 192-193 unlocks the enzyme, which displays chymase activity, and proteomic analysis confirms that activity of the wild-type protease can be released through interactions with an appropriate substrate. The 2.5-Å structure of the unlocked enzyme reveals unprecedented flexibility in the 190-strand preceding the active-site serine that results in Phe-191 vacating the S1 pocket. Overall, these observations describe a broadly applicable mechanism of protease regulation that cannot be predicted by template-based modeling or bioinformatic approaches alone.protease regulation ͉ register shift ͉ allostery P roteolysis plays an essential role in many biological pathways, an importance that is emphasized by the wide range and diversity of proteases that account for Ϸ2-3% of the human proteome (1). Of these, the largest group is the primary specificity (S1) family of serine proteases whose active sites contain three distinct features. The first is the catalytic triad (H57, D102, and S195 in chymotrypsin numbering) that creates a nucleophile to attack the substrate peptide bond. Mutation of any of these residues abolishes activity. Second is the ''oxyanion hole'' created by the main chain amide groups of S195 and G193. The positive charge in this region neutralizes a negatively charged oxygen atom in the substrate that is transiently formed during catalysis. Last, a conserved salt bridge is formed between the N-terminal amine group and the side chain of D194. This interaction introduces constraints on the active-site architecture that aid in cleavage efficiency.Given the diversity of irreversible effects that serine proteases can have on a variety of biological pathways, their actions are tightly regulated. During biosynthesis, most serine proteases follow a one-step activation pathway involving precursor processing. They are initially synthesized as inactive precursors (zymogens) in which the active site is unformed. Limited proteolysis at the N terminus removes the inactivating propeptide, thus allowing the protease to fold into a mature, active state. Once activated, serine proteases are controlled by a variety of inhibitors that may be either specific (for example, inhibitors of the serpin family) or nonspecific (such as ␣ 2 -macroglobulin) to ensure that they exert their effects only within the correct context. (3) or other proteins (4). This results in a two-step active-site assembly pathway for activation, from the ...

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Nephritogenic T cells use granzyme C as a cytotoxic mediator

Cited by 19 publications

References 46 publications

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8⁺T cells in influenza virus-infected mice

Structure of granzyme C reveals an unusual mechanism of protease autoinhibition

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Nephritogenic T cells use granzyme C as a cytotoxic mediator

Cited by 19 publications

References 46 publications

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+T cells in influenza virus-infected mice

Structure of granzyme C reveals an unusual mechanism of protease autoinhibition

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Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8⁺T cells in influenza virus-infected mice