Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

Clinical severe T-cell immunodeficiencies (in many cases accompanied by deficiencies of other lymphocyte populations) are known to be caused by mutations in almost 40 different genes. These genes encode products vital for processes such as cytokine and T-cell receptor (TCR) signalling, V(D)J recombination and antigen presentation.T-cell immunodeficiencies may not always be absolute, and in many cases an immunodeficient patient may also have symptoms of immune dysregulation, such as autoimmunity. In certain cases, identical mutations can cause severe or partial T-cell immunodeficiency, highlighting the complexity of pathogenesis.For both severe and partial T-cell immunodeficiencies in humans, there are multiple genetic and/or phenotypic counterparts in mice, which are proving invaluable as tools to dissect cellular and biochemical mechanisms of these disorders.Studies of these models have revealed that multiple T-cell tolerance mechanisms are population sensitive. These mechanisms, including thymic negative selection, peripheral suppression by FOXP3+ regulatory T cells and peripheral activation of effector T cells, show reduced efficacy at low T-cell population densities regardless of the properties of individual T cells.Many common variant alleles (in genes such as PTPN22 (protein tyrosine phosphatase, non-receptor type 22) and IL7RA (interleukin-7 receptor α-chain)) have been reproducibly associated with multiple common autoimmune diseases. We propose that a proportion of such alleles (and also rare alleles not detected by genome-wide association studies) contribute to common autoimmune diseases by creating a state of partial T-cell immunodeficiency, which is insufficient in itself to promote autoimmunity but can synergize to promote the activation of self-reactive T cells.