title: IL-2 gene knockout affects T lymphocyte trafficking and the microglial response to regenerating facial motor neurons.
abstract: Following facial nerve axotomy in mice, T cells cross the intact blood-brain barrier (BBB), home to nerve cell bodies in the facial motor nucleus (FMN), and augment neuroregenerative processes. The pivotal T cell immunoregulatory cytokine, IL-2, appears to have bidirectional effects on neuronal and microglial cell function, suggesting rival hypotheses that IL-2 could either enhance or disrupt processes associated with regeneration of axotomized facial motor neurons. We tested these competing hypotheses by comparing the effect of facial nerve axotomy on C57BL/6-IL-2(-/-) knockout and C57BL/6-IL-2(+/+) wild-type littermates. Since IL-2 may also be produced endogenously in the brain, we also sought to determine whether differences between the knockout and wild-type mice were attributable to loss of IL-2 gene expression in the CNS, loss of peripheral sources of IL-2 and the associated effects on T cell function, or a combination of these factors. To address this question, we bred novel congenic mice with the SCID mutation (mice lacking T cell derived IL-2) that were homozygous for either the IL-2 knockout or wild-type gene alleles (C57BL/6scid-IL-2(-/-) and C57BL/6scid-IL-2(+/+) littermates, respectively). Groups were assessed for differences in (1) T lymphocytes entering the axotomized FMN; (2) perineuronal CD11b(+) microglial phagocytic clusters, a measure of motor neuron death; and (3) activated microglial cells as measured by MHC-II positivity. C57BL/6-IL-2(-/-) knockout mice had significantly higher numbers of T cells and lower numbers of activated MHC-II-positive microglial cells in the regenerating FMN than wild-type littermates, although the number of CD11b(+) phagocytic microglia clusters did not differ. Thus, despite the significant impairment of T cell function known to be associated with loss of peripheral IL-2, the increased number of T cells entering the axotomized FMN appears to have sufficient activity to support neuroregenerative processes. Congenic C57BL/6scid-IL-2(-/-) knockout mice had lower numbers of CD11b(+) microglial phagocytic clusters than congenic C57BL/6scid-IL-2(+/+) wild-type littermates, suggesting that loss of the IL-2 gene in the CNS (and possibly the loss of other unknown sources of the gene) enhanced neuronal regeneration. Further study of IL-2's complex actions in neuronal injury may provide greater understanding of key variables that determine whether or not immunological processes in the brain are proregenerative.
authors.affiliation: Department of Psychiatry, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610-0256, USA. jpetitto@ufl.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Petitto
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lo
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Streit
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000235:genetics* / Q000276:immunology; D005154:Facial Nerve / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020220:Facial Nerve Injuries / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009416:Nerve Regeneration / Q000235:genetics* / Q000276:immunology; D012183:Retrograde Degeneration / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2