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Positive and negative influences of regulatory T cells in generating the naïve T cell compartment

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Host: Nick Holmes,

Mechanisms that control the size of the T cell pool, the ratio between naïve 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 shown that a subset of naïve CD4 T cells, defined by the expression on their surface of a very low density of CD44 (CD44v.low cells) are extremely efficient in creating a T cell pool with a diverse TCR repertoire, generating regulatory T cells that express Foxp3, and promoting a large naïve cell population that is present in homeostatic equilibrium with memory and Foxp3 regulatory T cell (Treg) numbers. The data support a key role for CD4 CD44v.low cells as peripheral precursors that maintain the integrity of the CD4 T cell pool.

This finding is significant because prior to this study, it was a well-established paradigm that the naïve cell compartment could only be generated by thymopoiesis. We further challenge that paradigm by showing that conventional naïve cells can also reconstitute a naïve cell compartment in lymphopenic hosts by manipulating their composition of thymus-derived natural nTregs and peripherally derived acquired aTregs. Thus, the ability of conventional naïve cells to repopulate the naïve cell compartment is negatively influenced by nTregs, and, in the absence of nTregs, positively influenced by aTregs. Mechanistic studies show alternative cytokine pathways for Treg function in promoting and inhibiting naïve cell reconstitution culminating in changes in the cell surface expression of CD44 and the interleukin-7 receptor respectively.

Understanding the apparently opposing roles of aTregs and nTregs in establishing and maintaining a functional CD4 + T cell compartment will be important in the design of therapeutic strategies to establish or re-establish immune homeostasis in conditions of lymphopenia and immune dysregulation, respectively.

This talk is part of the Immunology in Pathology series.

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