Scientists identify immune-system mutation

Feb 27 2005

A team of Fox Chase Cancer Center scientists led by immunologist Dietmar J. Kappes, Ph.D., has identified the genetic mutation that keeps a mouse strain from developing white blood cells, or lymphocytes, called helper T cells. The report by Kappes and his colleagues appears in the Feb. 24 issue of Nature.

Kappes' laboratory first discovered the mice with this naturally occurring defect in Fox Chase's laboratory animal facility in 1997. Known as "helper deficient" or HD mice, they are proving to be useful for exploring the pathways of lymphocyte development, according to Kappes.

Helper T cells, so called because they arise from the thymus gland, are essential for combating intracellular viral and bacterial infections (cell-mediated immunity) and also for helping other white blood cells (B cells, derived from bone marrow) generate antibodies against foreign agents that enter the body. Other T cells are known as killer cells because they attack foreign invaders more directly.

"The maturation of T cells involves key branch points at which cells choose one of two different pathways, going on to become helper cells or killer cells," Kappes said. His goal is to understand how T cells specialize to do different jobs.

Commitment to the helper or killer lineages correlates precisely with the restriction of the T-cell receptor toward either class I or class II major histocompatibility complex (MHC) molecules. Most helper T cells carry a surface protein called CD4, which is attracted to class II MHC. Killer cells carry the CD8 protein, attracted to class I MHC. However, the underlying molecular pathways that regulate this process have remained obscure.

"The mutant HD mice are unable to generate mature helper T cells, even though their immature T cells carry the CD4 protein," Kappes explained. "Instead, the mutation redirects them to the killer-cell pathway.

"Our new study identifies this defect as a point mutation in the zinc finger transcription factor Th-POK. We show that when the normal form of this factor is active in all developing lymphocytes, it can redirect would-be killer cells to the CD4 helper T cell lineage. This indicates that Th-POK is a master regulator of the maturation process."

Understanding the development of critical components of the immune system can contribute to medical advances in stimulating desirable immune responses and halting undesirable immune reactions, Kappes said. This understanding can further progress against various immune disorders, allergies and certain cancers, such as those of the blood and bone marrow, that involve a compromised immune system.

"As one example, a decrease in the number of CD4 T cells is the primary mechanism by which HIV causes AIDS," Kappes said.

The helper-deficient mice his team discovered represent the second time that a naturally occurring mutant strain has been found and bred at Fox Chase. In 1981, the laboratory group of Melvin Bosma, Ph.D., discovered mice with severe combined immune deficiency (SCID), a condition that also affects humans. In addition to providing a unique animal model to study the SCID syndrome, SCID mice have become a highly valuable tool for studying the immune system and are now used by scientists worldwide.

Kappes' co-authors on the new Nature paper include Fox Chase postdoctoral associates Xiao He, Ph.D., Xi He, Ph.D., and Vibhuti P. Dave, Ph.D., (who is now at the Institute of Clinical Research of Montreal); Fox Chase scientific technician Yi Zhang; Xiang Hua, manager of Fox Chase's transgenic mouse facility; Fox Chase research associate Emmanuelle Nicolas, Ph.D.; and Weihong Xu, Ph.D., and Bruce A. Roe, Ph.D., both of the University of Oklahoma's department of chemistry and biochemistry.