Autoimmunity: The more the merrier

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Homeostatic expansion of T cells during immune insufficiency generates autoimmunity.

In a surprising new study published in Cell, Nora Sarvetnick and colleagues have shown that autoimmunity can be caused by insufficient numbers of T cells. This indicates that having a crowded immune system can actually be good for you and provides an explanation for the beneficial effects of a 'less-than-hygienic' environment.

They showed that female autoimmune-prone non-obese diabetic (NOD) mice have fewer peripheral CD4⁺ T cells than control strains that do not develop autoimmunity. This lymphopaenia was associated with disease development, as increasing the number of T cells in NOD mice by injection of complete Freund's adjuvant (CFA; which contains T-cell stimulatory mycobacterial cell-wall components) protected the mice from developing diabetes. Furthermore, the effect was due to T-cell number rather than phenotype as the transfer of T cells from NOD littermates also prevented diabetes.

The artificial induction of lymphopaenia — for example, by irradiation — results in proliferation of the remaining T cells to fill the 'space' that is left. To see if this homeostatic expansion occurs in NOD mice, the authors monitored labelled NOD T cells expressing a T-cell receptor (TCR) specific for pancreatic beta -cells after transfer to various hosts. These TCR-transgenic T cells only proliferated in lymphopenic NOD mice and not in NOD mice treated with CFA. Analysis of cell-surface markers such as CD62L to distinguish between classically activated and homeostatically expanding T cells was also used to show that a far greater percentage of the natural T-cell populations of NOD mice are undergoing homeostatic expansion compared with non-lymphopenic, non-autoimmune-prone mice. Importantly, NOD mice with the most proliferating T cells had the most severe pancreatic insulitis, which indicates that there is a direct link between homeostatic expansion and disease.

Part of the explanation for the lymphopenia of NOD mice might lie in the observation that they have increased levels of IL-21 production, leading to upregulation of interleukin-21 receptor (IL-21R) expression by T cells, and clear evidence of increased responsiveness to this cytokine. IL-21 is a recently identified member of the gamma c cytokine family, other members of which (such as IL-7) mediate T-cell proliferation and survival. However, in contrast to IL-7, IL-21 did not support the survival of T cells in vitro. The IL-21R⁺ T cells of NOD mice proliferate rapidly but do not survive, leading to low numbers of long-lived memory T cells. The observation that stimulated T cells have a short life was supported by their failure to upregulate expression of the anti-apoptotic molecules Bcl-2 or Bcl-X_L. The important role of IL-21 in autoimmune susceptibility in this model ties in with the fact that the gene encoding IL-21 lies in a known NOD susceptibility locus on chromosome 3.

Sarvetnick and colleagues suggest that a lymphopenic environment favours the proliferation of those T cells specific for readily available antigens. In most cases, this will be autoreactive T cells that have escaped deletion in the thymus. Being 'too clean', particularly during childhood, could create such a lymphopenic environment in humans by reducing the constant stimulation of our immune systems by bacteria and viruses in the environment. This could explain the increasing prevalence of autoimmune diseases in modern 'hygienic' societies.

Kirsty Minton

References

King, C. et al. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265–277 (2004) | Article | PubMed |