Atypical memory phenotype T cells with low homeostatic potential and impaired TCR signaling and regulatory T cell function in Foxn1Delta/Delta mutant mice.
Foxn1Delta/Delta mutants have a block in thymic epithelial cell differentiation at an intermediate progenitor stage, resulting in reduced thymocyte cellularity and blocks at the double-negative and double-positive stages. Whereas naive single-positive thymocytes were reduced >500-fold in the adult Foxn1Delta/Delta thymus, peripheral T cell numbers were reduced only 10-fold. The current data shows that Foxn1Delta/Delta peripheral T cells had increased expression of activation markers and the ability to produce IL-2 and IFN-gamma. These cells acquired this profile immediately after leaving the thymus as early as the newborn stage and maintained high steady-state proliferation in vivo but decreased proliferation in response to TCR stimulation in vitro. Single-positive thymocytes and naive T cells also had constitutively low alphabetaTCR and IL7R expression. These cells also displayed reduced ability to undergo homeostatic proliferation and increased rates of apoptosis. Although the frequency of Foxp3+CD4+CD25+ T cells was normal in Foxn1Delta/Delta mutant mice, these cells failed to have suppressor function, resulting in reduced regulatory T cell activity. Recent data from our laboratory suggest that T cells in the Foxn1Delta/Delta thymus develop from atypical progenitor cells via a noncanonical pathway. Our results suggest that the phenotype of peripheral T cells in Foxn1Delta/Delta mutant mice is the result of atypical progenitor cells developing in an abnormal thymic microenvironment with a deficient TCR and IL7 signaling system.
Department of Genetics, University of Georgia, Athens, GA 30602, USA.
Shiyun
S
Xiao
Dong-ming
DM
Su
Nancy R
NR
Manley
D000818:Animals; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics*; D006706:Homeostasis; D007156:Immunologic Memory / Q000235:genetics*; D015851:Interleukin-7 / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D051858:Forkhead Transcription Factors; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; C090140:Whn protein