Cytokine networks in human severe combined immunodeficiency: a model for regulating T-cell homeostasis
© The Author(s) 2004
Published: 13 September 2004
Human T-lymphocyte homeostasis is a complex process wherein the number of T lymphocytes is held relatively constant in normal individuals. How the body senses the numbers of circulating T-cells and regulates their expansion and survival is unclear. We sought to better understand this process by profiling serum cytokines in severe combined immunodeficiency (SCID) before and after T-cell reconstitution with bone marrow transplantation.
We used a novel protein microarray technology to simultaneously measure the levels of 78 different soluble proteins in the serum of 10 normal subjects and 31 SCID subjects before and at various times after transplantation. We used a linear mixed analysis of variance model and novel SAS graphics tools to identify factors that were altered in SCID and changed in response to T-cell engraftment.
We identified that IL-15 > MCP-1 > HCC4 > IL-7 were over-expressed in SCID patients before transplantation at times when there were few circulating T cells (P < 0.001 compared with controls). Both IL-7 and IL-15 normalized after successful transplantation with normal levels of circulating T cells, but not after failed transplants. HCC4 and MCP-1 levels remained high despite transplantation. Levels of nine growth factors were decreased and levels of six proinflammatory cytokines were increased after successful transplantation for SCID.
Our studies in a human model of aberrant T-lymphocyte homeostasis wherein IL-15 and, to a lesser extent, IL-7 levels inversely correlate with circulating T-lymphocyte levels provide evidence that IL-15 and IL-7 may regulate human T-lymphocyte homeostasis. In addition, the downmodulation of numerous growth factors and upregulation of proinflammatory cytokines after successful T-cell reconstitution identify factors other than IL-15 and IL-7 that may be involved in the sensing and regulation of T-lymphocyte homeostasis in man.