IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition.
The interleukin (IL)-12p40 family of cytokines plays a critical role in the development of experimental autoimmune encephalomyelitis (EAE). However, the relative contributions of IL-12 and IL-23 to the pathogenic process remain to be elucidated. Here, we show that activation of uncommitted myelin-reactive T cells in the presence of either IL-12p70 or IL-23 confers encephalogenicity. Adoptive transfer of either IL-12p70- or IL-23-polarized T cells into naive syngeneic hosts resulted in an ascending paralysis that was clinically indistinguishable between the two groups. However, histological and reverse transcription-polymerase chain reaction analysis of central nervous system (CNS) tissues revealed distinct histopathological features and immune profiles. IL-12p70-driven disease was characterized by macrophage-rich infiltrates and prominent NOS2 up-regulation, whereas neutrophils and granulocyte-colony-stimulating factor (CSF) were prominent in IL-23-driven lesions. The monocyte-attracting chemokines CXCL9, 10, and 11 were preferentially expressed in the CNS of mice injected with IL-12p70-modulated T cells, whereas the neutrophil-attracting chemokines CXCL1 and CXCL2 were up-regulated in the CNS of mice given IL-23-modulated T cells. Treatment with anti-IL-17 or anti-granulocyte/macrophage-CSF inhibited EAE induced by transfer of IL-23-polarized, but not IL-12p70-polarized, cells. These findings indicate that autoimmunity can be mediated by distinct effector populations that use disparate immunological pathways to achieve a similar clinical outcome.
Department of Neurology, Holtom-Garrett Program in Neuroimmunology, University of Michigan, Ann Arbor, MI 48109, USA.
Mark A
MA
Kroenke
Thaddeus J
TJ
Carlson
Anuska V
AV
Andjelkovic
Benjamin M
BM
Segal
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015551:Autoimmunity / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D019743:Chemokines, CXC / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D010243:Paralysis / Q000276:immunology / Q000473:pathology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D000906:Antibodies; D019743:Chemokines, CXC; D020381:Interleukin-17; D053759:Interleukin-23; D011506:Proteins; C034911:serum cancer-suppressive peptide, mouse; D018664:Interleukin-12; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse