Trends in Immunology
OpinionCD24: a genetic checkpoint in T cell homeostasis and autoimmune diseases
Introduction
Because of its extreme resistance to heat-inactivation, CD24 was originally called the heat-stable antigen [1]. Since its initial discovery in 1978, CD24 has been used extensively to study differentiation of hematopoietic cells and neuronal cells, in addition to tissue and tumor stem cells. Its wide distribution, matched only by its biochemical heterogeneity, has made it difficult to assign a unique function to CD24. By contrast, it is perhaps more likely that the product encoded by the CD24 gene has a diverse function depending both on its composition and its cellular environment. Emerging data reveal a pivotal role for CD24 in T cell homeostasis and pathogenesis of autoimmune diseases.
Section snippets
The link between immune deficiency and autoimmune diseases – a paradox
Although autoimmune disease is generally regarded as over-activation of the immune system so that it turns against the normal tissues, it is a long-standing clinical observation that patients with autoimmune diseases are severely immune deficient, and multiple organ inflammation often accompanies repeated infection. Autoimmune patients often have a reduced number of lymphocytes, including T cells. The reduction in T cell numbers can be caused by an increased death of mature T cells or by a
Homeostatic proliferation in response to lymphopenia – a possible mechanism to reconcile the paradox
A possible resolution of the paradox is emerging from the studies of lymphopenia-driven homeostatic proliferation of T cells. The immune system maintains a relatively constant number of lymphocytes by two distinct mechanisms. Activation-induced cell death 17, 18 results in the removal of a large number of lymphocytes after massive antigen-induced clonal expansion. When the lymphocytes are depleted, naive T cells undergo rapid expansion to replenish the T lymphocyte pool 19, 20. This phenomenon
CD24 – genetics and biological function
CD24 was first identified in 1978 when Springer produced xenogeneic rat anti-mouse antibodies M1/69 and M1/75. Because of its resistance to heat, he termed it the ‘heat-stable antigen’ [1]. CD24 is highly immunogenic in xenogeneic animals as several groups have generated antibodies that react with the heat-stable antigen 32, 33, 34. The heat-stable antigen is expressed as a glycosylphosphatidylinositol (GPI)-anchored molecule [35] and has a wide distribution in different lineages [36]. For this
CD24 in autoimmune diseases
Surprisingly, when mice with a targeted mutation of CD24 were tested for the development of experimental autoimmune encephalomyelitis (EAE), we observed that CD24-deficiency conferred resistance to EAE [57]. Using the myelin oligodendrocyte glycoprotein peptide 35–55-induced EAE model, we demonstrated that mice with a targeted mutation of CD24 are completely resistant to induction of EAE. Although several genes have been reported to be essential for the development of EAE, CD24 is unique in
CD24 and the control of T cell homeostatic proliferation
Given the broad function of CD24 in the pathogenesis of multiple autoimmune diseases, understanding the immunological mechanisms for CD24 involvement will not only reveal an important function of CD24, but also reveal novel checkpoints of autoimmune diseases. Serendipitously, we found that when we transferred WT and CD24-deficient T cells into irradiated lymphopenic hosts, we observed that WT T cells spontaneously divided whereas CD24-deficient T cells failed to do so. By contrast, both WT and
Concluding remarks
Autoimmune disease and T cell homeostasis are two inter-related but poorly defined processes. The identification of a common checkpoint such as CD24 helps to establish a genetic link between the two. Analysis of CD24 function also suggests a plausible immunological basis for the CD24-mediated pathogenesis of autoimmune diseases, including costimulating antigen-driven proliferation in nonlymphoid organs, and, in the lymphoid organs, homeostatic proliferation and perhaps the survival and
Acknowledgements
We thank our collaborators, Xue-feng Bai, Lizhong Wang, Ou Li, Xing Chang, Qunmin Zhou, Shili Lin, Kottil Rammohan, Jin-qing Liu and Chack Y. Yu, who contributed substantially to the research that forms the basis of this article. This work is supported by grants from the National Institute of Health, USA.
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