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Abstract

This invention relates to methods and systems for measuring T cell diversity. It is particularly related to methods of identifying T cell receptor (TCR) pairs and their relative frequencies and finds particular use in antigen-specific T cell populations and other T cell populations with limited polyclonality. An exemplary embodiment of the invention provides a method estimating the clonal composition of a T cell population, the method including the steps of: obtaining a plurality of samples from said population, each sample containing a plurality of T cells; sequencing the CDR3α and CDR3β regions of each of those samples; calculating, for every α and β chain found in common in at least one of the samples, an association score which reflects the likelihood of pairing between each of those chains; repeatedly, for a randomly selected subset of said samples, determining, from the calculated association scores, the most likely αβ pairs in each of said selected samples and selecting those pairs as candidate αβ pairs; comparing the number of instances that each of said candidate αβ pairs appears in all of said repeats to a threshold and selecting those pairs whose instances exceed said threshold as true αβ pairs; estimating, from the frequency of co-existence of α and β chains in each of said samples and the sample size of said sample, the frequency of each of said true αβ pairs; and discriminating, amongst said αβ pairs, between possible dual T cell receptors or two clones which share a common β chain.

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First Claim