They concluded that there is an initial low threshold of activation permitting the recruitment of both high (best-fit Vα) and low (less ideal Vα) affinity TCRs into the early stages of the immune response. How does the immune system ensure the selection of a diverse, yet high avidity TCR repertoire? Malherbe et al fixed the TCRβ-chain for I-E k/pigeon cytochrome C peptide (PCC 81-104)-specific CD4 + T cells, then determined the extent of pre- and post-immune I-Ek/PCC 81-104-specific TCR repertoire diversity by analysing the spectrum of CDR3α sequences utilized by these TCRβ-transgenic CD4 + T cells. Preferential selection of higher avidity TCRs in an immune response Overall, the stochastic nature of T cell functional acquisition looks to be broadly independent of TCR diversity. Functional capacity may, in fact, be determined primarily by the extent of T cell division,, as heterogeneity of effector phenotype can be characteristic of a single, antigen-specific clone during an infectious process. The effect has been shown for TCR-diverse endogenous responses and for adoptively transferred CD4 + and CD8 + transgenic T cells. Maturing T cell responses can “evolve” to a state of increased “functional avidity” as determined by the capacity to respond to lower concentrations of peptide. Furthermore, mature D bPA 224 – and D bNP 366- specific CTLs have identical profiles of perforin and granzyme mRNA expression, indicating that the acquisition of cytotoxicity is not modulated by differences in TCR repertoire diversity. This suggests that functional quality is not dictated by TCR usage within antigen-specific CTL. Recent TCRVβ repertoire analysis demonstrated no difference in clonotype usage between of single and multiple cytokine producers within both the D bNP 366 and D bPA 224-specific CTLs (NLG, ST, unpublished data). However, analysis of T cells specific for the influenza D bPB1-F2 epitope suggests that there is no link between TCR diversity and multiple cytokine production. But it isn't always that simple.Īfter influenza A virus infection, the essentially “private”, TCR-diverse and higher avidity D bPA 224 –specific CD8 + cytotoxic T lymphocyte (CTL) population has a greater capacity for inflammatory cytokine production than the more TCR-constrained, substantially “public” D bNP 366-specific CTL set. Intuitively, selection of a diverse TCR repertoire might be thought to enhance functional heterogeneity, with the high avidity T cells being the more potent effectors. Affinity/avidity is clearly the gatekeeper determining the necessary level of “fitness”, or signaling threshold, for the recruitment and emergence of any given T-cell clone in a particular immune response. The affinity of an individual binding event translates to avidity as multiple TCR/pMHC engagements mediate the T lymphocyte/antigen presenting cell (APC) interaction. Ideally, these signals are integrated to ensure optimal proliferation and the acquisition of effector function and memory. TCR diversity and functional heterogeneity within a given repertoireĪctivation of naïve T cells requires i) TCR/pMHC ligation (signal 1) ii) co-stimulation (signal 2) and iii) inflammatory cytokines (signal 3). While many factors can shape TCR diversity of immune T cell populations, it is less clear how T cell diversity imparts effective immunity. Different V gene segment combinations, combinatorial and junctional variation within the CDR3α and CDR3β regions and the addition of non-templated nucleotides at the V(D)J junctions all contribute to the diversity observed within the naïve TCR repertoire. While the CDR1 and 2 regions are germline, the CDR3 region is generated after VJ and VDJ gene recombination. Multiple TCR Vα, Jα, Vβ, Dβ and Jβ segments within the TCR locus are generated via random splicing of TCR gene segments during T cell development and antigen-specificity is imparted by the hypervariable complementarity-determining regions (CDRs) encoded within the V gene segments. The Vβ-region is a combination of variable (V), diversity (D) and junctional (J) gene segments, whereas V and J gene segments encode the Vα-chain. Each TCR chain contains a variable (V) and constant (C) region.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |