Event:272

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Event Title

T-cells, Activation/Proliferation
Short name: T-cells, Activation/Proliferation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Skin Sensitisation Initiated by Covalent Binding to Proteins KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

Since the final stage in the sensitisation phase is the activation of naive T-lymphocytes in the local lymph node, an in vitro assay based on T-cells are useful in confirming the AOP as well as identifying sensitizers. As noted earlier, T-cells are typically activated to form a memory T-cell by protein-hapten complexes presented by dendritic cells on a MHC molecule. Molecular understanding of this process has improved in recent years[1]. Most protocols recognize the importance of the process of antigen presentation, so in vitro T-cell-based assays are typically co-cultures of allergen-treated dendritic cells and modified T-lymphocytes with expression of selected biomarkers (e.g., interferon gamma), or Tcell proliferation being the reported outcome. Much of this work has been recently reviewed by Martin et al. ([1]). It should be remembered that lymph node cell proliferation is the basis for the LLNA.

T-cells are typically affected by protein-hapten complexes presented by dendritic cells on MHC molecules. Molecular understanding of this process has improved in recent years (see [1]). Briefly, MHC molecules are membrane proteins which present the small peptide antigens placed in a “groove” of the MHC molecule during its intracellular synthesis and transport to the cell surface. In the context of the MHC molecular on the cell surface, the small peptide antigen is recognized via the T-cell receptors as self or non-self (e.g. foreign). If this peptide is a foreign peptide, such as part of a proteinhapten complex, the T-cell will be activated to form a memory T-cell, which subsequently proliferates. If reactivated upon hapten presentation by skin dendritic cells, these memory T-cells will induce allergic contact dermatitis[2].

Perhaps the most interesting finding about lymphoid tissue, as related to the sensitisation is the selectivity of cytokine secretion. Hopkins et al.[3]), building on earlier work of Dearman and coworkers, reported that lymphoid tissue of mice exposed to classic electrophiles with conjugate proteins via 36 nucleophilic substitution as halo-nitro-aromatic compounds (i.e. 1-chloro-2,4-dinitrobenzene and 1-fluoro- 2,4-dinitrobenzene) expresses high levels of the Th1 cytokine IFN-γ and low levels of the Th2 cytokines IL-5 and IL-10. Conversely, lymphoid tissue for mice exposed to 2,4-dinitrobenzene sulphonyl chloride, which conjugates with proteins via nucleophilic substitution as a sulphonyl halides, the acylating agent trimellitic anhydride, or fluorescein isothiocyanate, which conjugates with proteins via nucleophilic addition to the carbon atom of the isothiocyanate (-N=C=S) moiety, express high levels of the Th2 cytokines IL-5 and IL-10 and low levels of the Th1 cytokine IFN-γ. Based on differential binding to cellular and serum proteins Hopkins et al. ([3]) showed that chemicals that stimulate a Th1 cytokine response bind selectively to cellular proteins, while chemicals that stimulate a Th2 cytokine response bind selectively to serum proteins. While it would be tempting to say electrophiles which preferentially bind to cysteine express a Th1 cytokine profile and electrophiles which preferentially bind to lysine express a Th2 cytokine profile, it is most likely not that simple.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Recognizing the importance of the process of antigen presentation (i.e. T-cell priming), in vitro T-cell priming assays have been developed (see[1]). While first generation assays could only detect strong or extreme sensitizers, more recent development using normal human peripheral blood depleted of regulatory cells that normally prevent the sensitisation phase increased the probability that T-cell proliferation would be detected [4]). A related approach is based on the hypothesis that there is a correlation between the potency of contact allergens and T-cell frequency and T-cell receptor repertoire ([5]). It is plausible that sensitisation potency may correlate with the size of the contact allergen-specific effector and regulatory T-cell pools and their diversity, and this could form the basis of a new generation of in vitro T-cell priming assays. It should be remembered that lymph node cell proliferation is the basis for the LLNA.

Evidence Supporting Taxonomic Applicability

References

  1. 1.0 1.1 1.2 1.3 Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F. 2010. T-cell recognition of chemical, protein allergens and drugs; toward the development of in vitro assays. Cell. Mol. Life Sci. 67: 4171-4184.
  2. Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.
  3. 3.0 3.1 Hopkins JE, Naisbitt DJ, Kitteringham NR, Dearman RJ, Kimber I, Park BK. 2005. Selective haptenation of cellular or extracellular proteins by chemical allergens: Association with cytokine polarization. Chem. Res. Toxicol. 18: 375-381.
  4. Cite error: Invalid <ref> tag; no text was provided for refs named Vocanson
  5. Kotturi MF, Scott I, Wolfe T, Peters B, Sidney J, Cheroutre H, et al. 2008. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J. Immunol. 181: 2124-2133.