A peripheral CD4+ T cell precursor for naive, memory, and regulatory T cells

Mechanisms that control the size of the T cell pool, the ratio between naive cells and memory cells, the number and frequency of regulatory T cells, and T cell receptor (TCR) diversity are necessary to maintain immune integrity and avoid disease. We have previously shown that a subset of naive CD4(+) T cells, defined by the expression on their surface of a very low density of CD44 (CD44(v.low) cells), can inhibit wasting and wasting-associated lymphopenia in mice with cancer. In this study, we further investigate the properties of CD44(v.low) cells and show that they are significantly more efficient than the remaining naive (CD44(low) or CD44(int)) and memory CD4(+) cell subsets in reconstituting the overall size of the CD4(+) T cell pool, creating a T cell pool with a diverse TCR repertoire, generating regulatory T cells that express forkhead box P3 (FoxP3), and promoting homeostatic equilibrium between naive, memory, and Foxp3(+) regulatory T cell numbers. T cell population reconstitution by CD44(v.low) cells is thymus independent. Compared with CD44(int) cells, a higher percentage of CD44(v.low) cells express B cell leukemia/lymphoma 2, interleukin-7 receptor, and CD5. The data support a key role for CD4(+) CD44(v.low) cells as peripheral precursors that maintain the integrity of the CD4(+) T cell pool.