8/15/2023 0 Comments Dna vs rna tcr repertoire![]() In the periphery, naive T cells compete for cytokines, such as IL-7, and need to interact with self-pMHC to survive ( Tanchot et al., 1997 Takada and Jameson, 2009 Jenkins et al., 2010). The thymic output of new T cells decreases because of thymic involution, making peripheral division of existing cells the main source of naive T cells from early adulthood onwards in humans ( den Braber et al., 2012 Kumar et al., 2018). About 3–5% of thymocytes survive selection ( Merkenschlager et al., 1997) and enter the periphery as T cells that have not yet encountered foreign cognate antigen, that is as naive T cells. After generation of the TCR, T cells undergo positive and negative selection, which selects those T cells that have sufficient, but not too high, affinity for any self-pMHC ( McDonald et al., 2015). Recent estimates of the potential number of TCRs produced by this V(D)J-recombination process range from > 10 20 ( Zarnitsyna et al., 2013) to 10 61 ( Mora and Walczak, 2019), which vastly outnumbers the number of distinct TCRs present in a human body. Most variability arises due to random nucleotide insertions and deletions where the segments are joined ( Murugan et al., 2012). This heterodimer is generated by random recombination of Variable, Diversity, and Joining (V, D and J) segments for TCRβ, and V and J segments for TCRα sequences ( Davis and Bjorkman, 1988). Generation of αβ TCRs occurs in the thymus, where thymocytes randomly rearrange and imprecisely recombine gene segments to create a complete receptor ( Nikolich-Zugich et al., 2004). The actual diversity of the TCR repertoire is unknown, but with improved sequencing techniques, estimates have risen by orders of magnitude from 10 6 ( Arstila et al., 1999), 10 7 ( Robins et al., 2009), to over 10 8 ( Qi et al., 2014). The TCR has to be specific to distinguish between self- and non-self-pMHC, but due to the large number of possible foreign antigens (> 20 9) a specific TCR is nevertheless expected to bind many different pMHC (i.e., cross-reactivity) ( Mason, 1998 Sewell, 2012). Most T cells express a single T-cell receptor (TCR) variant, which binds antigen in the form of a short peptide presented by the Major Histocompatibility Complex (pMHC) ( Davis and Bjorkman, 1988). The human adaptive immune system employs a vast number (> 10 11 ) of T lymphocytes, to detect and control pathogens. TCRα abundant sequences can be primarily attributed to many identical recombination events in different cells, while abundant TCRβ sequences are primarily derived from large clones, which make up a small percentage of the naive repertoire, and could be established early in the development of the T-cell repertoire. By combining experimental data with predictions from models we describe two mechanisms contributing to TCR sequence abundance. We detect abundant TCR sequences even after exclusion of methodological confounders such as sort contamination, and multiple mRNA sampling from the same cell. However, a substantial number of sequences were observed multiple times. We observe most TCR sequences only once, consistent with the enormous diversity of the repertoire. We estimated the abundance of TCR sequences in samples of naive T cells from blood using an accurate quantitative sequencing protocol. The clone size distribution of the human naive T-cell receptor (TCR) repertoire is an important determinant of adaptive immunity. ![]()
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