# How many different clonotypes do immune repertoires contain?

## TL;DR

This paper reviews estimates of immune receptor diversity, highlights limitations of current methods in capturing small clone populations, and proposes combining statistical and mechanistic models to better estimate total clonotype numbers.

## Contribution

It identifies a key limitation in current diversity estimation methods and suggests a novel approach integrating statistical and mechanistic models.

## Key findings

- Current methods underestimate total clonotypes due to ignoring small clones.
- The tail of small clones significantly impacts diversity estimates.
- Combining models offers a promising strategy for accurate estimation.

## Abstract

Immune repertoires rely on diversity of T-cell and B-cell receptors to protect us against foreign threats. The ability to recognize a wide variety of pathogens is linked to the number of different clonotypes expressed by an individual. Out of the estimated $\sim 10^{12}$ different B and T cells in humans, how many of them express distinct receptors? We review current and past estimates for these numbers. We point out a fundamental limitation of current methods, which ignore the tail of small clones in the distribution of clone sizes. We show that this tail strongly affects the total number of clones, but it is impractical to access experimentally. We propose that combining statistical models with mechanistic models of lymphocyte clonal dynamics offers possible new strategies for estimating the number of clones.