Experimental allergic encephalomyelitis. T cell trafficking to the central nervous system in a resistant Thy-1 congenic mouse strain.
BACKGROUND
The understanding of recognition events that underlie the migration of antigen-specific T cells to a target organ during immune-mediated damage will be integral to the therapy of a number of human conditions of proven or suspected autoimmune etiology. In experimental allergic encephalomyelitis (EAE), the laboratory model of the human demyelinating disease, multiple sclerosis, previous studies have concentrated on susceptible strains and have shown that myelin-specific T cells play an early, key role in central nervous system (CNS), lesion formation. Not known in this model is whether in EAE-resistant strains, similar antigen-specific T cells possess the ability to recognize CNS endothelium and infiltrate the CNS.


METHODS
Myelin basic protein (MBP)-responsive T cells derived from mice of the C57BL/6 strain (bearing the Thy-1.2 allele) were adoptively transferred to the Thy-1.1 congenic strain C57BL/Ka. Some recipients were given a subsequent challenge with MBP in adjuvant, a protocol recently shown to break resistance in this strain and cause EAE. On the basis of the difference in Thy-1 allele, T cell trafficking was followed in this EAE-resistant congenic strain following the different sensitization protocols.


RESULTS
In C57BL/Ka mice receiving adoptively transferred C57BL/6 cells followed by MBP challenge, donor MBP-responsive Thy-1.2+ lymphocytes were detected by immunocytochemistry in the Thy-1.1 host CNS and also in peripheral lymphoid organs. In mice given MBP-sensitized cells without additional antigen challenge, although Thy-1.2+ cells were found in the spleen and lymph nodes, similar cells could not be found in the CNS, and animals displayed neither clinical nor pathologic signs of EAE. Donor T lymphocytes appeared in the host CNS with clinical onset, 10 to 14 days after challenge. When mice went into remission, Thy-1.2+ lymphocytes could not be found in the CNS, but were still present in peripheral lymphoid organs up to 3 months after challenge. From the total number of infiltrating cells, T cell receptor-alpha beta+ cells constituted 27% in perivascular cuffs, 15% in meninges, and 13% in the parenchymal infiltrates in the spinal cord. Thy-1.2+ cells contributed up to about 40% of total T cell receptor-alpha beta+ lymphocytes. Approximately 60% of all infiltrating T cells expressed L3T4 (helper/inducer), whereas 18% expressed Lyt-2 (suppressor/cytotoxic). The majority of infiltrating cells were memory and activated cells expressing on their surface Pgp-1 and CD 25. Immunostaining for cytokines showed that the majority of infiltrating cells belonged to the TH1 subset and contained interferon-gamma and tumor necrosis factor-alpha, while a minority were positive for interleukin-4.


CONCLUSIONS
These results suggest that: (a) T lymphocytes from an EAE-resistant strain of mouse are capable of homing to the CNS; (b) T lymphocytes from an EAE-resistant strain express phenotypic characteristics, activation, memory, and cytokine profiles similar to infiltrating cells derived from susceptible strains; and (c) the presence of donor T cells in the recipient CNS correlates with clinical and histopathologic signs of EAE.
Skundric
D S
DS
Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, New York.
Huston
K
K
Shaw
M
M
Tse
H Y
HY
Raine
C S
CS
D000818:Animals; D002490:Central Nervous System / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate; D007116:Immunization, Passive; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000276:immunology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D018800:Thy-1 Antigens / Q000276:immunology
D004676:Myelin Basic Protein; D016201:Receptors, Lymphocyte Homing; D018800:Thy-1 Antigens