TY - JOUR
T1 - Two discreet subsets of CD8 T cells modulate PLP 91-110 induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice
AU - Mangalam, Ashutosh K.
AU - Luckey, David
AU - Giri, Shailendra
AU - Smart, Michele
AU - Pease, Larry R.
AU - Rodriguez, Moses
AU - David, Chella S.
PY - 2012/6
Y1 - 2012/6
N2 - Previously we showed that transgenic mice expressing human HLA-DR3 gene are susceptible to PLP 91-110 induced experimental autoimmune encephalomyelitis (EAE) and can serve as an animal model of multiple sclerosis (MS). HLA-DR3 mice with EAE showed increased number of CD8 T cells indicating their important role in disease pathogenesis. The role of CD8 T cells in MS, an inflammatory demyelinating disease of CNS, has been enigmatic as it has been assigned both regulatory and pathogenic roles. Therefore, to evaluate the role of CD8 T cells, we generated CD8 deficient HLA-DR3 transgenic mice (DR3.CD8 -/-). Immunization with PLP 91-110 led to more severe EAE in DR3.CD8 -/- mice compared to HLA-DR3 mice indicating a regulatory role for CD8 T cells. Interestingly, DR3.CD8 -/- mice with EAE showed decreased CNS pathology compared to DR3 mice thus suggesting a pathogenic role for CD8 T cells. We show that these two subsets of CD8 T cells can be differentiated based on the surface expression of CD122 (IL-2 Rβ chain). CD8 T cells expressing CD122 (CD8+CD122+) play a regulatory role while CD8+CD122- T cells act as a pathogenic subset. CD122 expressing CD8 T cells are the regulatory subset of CD8 T cells and regulate the encephalitogenic CD4 T cells through direct modulation of antigen presenting cells and/or through the release of immunoregulatory cytokines such as IL-10, IFNγ and TGFβ. We also showed that adoptive transfer of CD8CD122- T cells caused increased spinal cord demyelination indicating that these are pathogenic subset of CD8 T cells. Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients.
AB - Previously we showed that transgenic mice expressing human HLA-DR3 gene are susceptible to PLP 91-110 induced experimental autoimmune encephalomyelitis (EAE) and can serve as an animal model of multiple sclerosis (MS). HLA-DR3 mice with EAE showed increased number of CD8 T cells indicating their important role in disease pathogenesis. The role of CD8 T cells in MS, an inflammatory demyelinating disease of CNS, has been enigmatic as it has been assigned both regulatory and pathogenic roles. Therefore, to evaluate the role of CD8 T cells, we generated CD8 deficient HLA-DR3 transgenic mice (DR3.CD8 -/-). Immunization with PLP 91-110 led to more severe EAE in DR3.CD8 -/- mice compared to HLA-DR3 mice indicating a regulatory role for CD8 T cells. Interestingly, DR3.CD8 -/- mice with EAE showed decreased CNS pathology compared to DR3 mice thus suggesting a pathogenic role for CD8 T cells. We show that these two subsets of CD8 T cells can be differentiated based on the surface expression of CD122 (IL-2 Rβ chain). CD8 T cells expressing CD122 (CD8+CD122+) play a regulatory role while CD8+CD122- T cells act as a pathogenic subset. CD122 expressing CD8 T cells are the regulatory subset of CD8 T cells and regulate the encephalitogenic CD4 T cells through direct modulation of antigen presenting cells and/or through the release of immunoregulatory cytokines such as IL-10, IFNγ and TGFβ. We also showed that adoptive transfer of CD8CD122- T cells caused increased spinal cord demyelination indicating that these are pathogenic subset of CD8 T cells. Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients.
KW - CD8 regulatory T cells
KW - Cytokine
KW - Demyelination
KW - Experimental autoimmune encephalomyelitis
KW - HLA class II transgenic mice
KW - Multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=84861193712&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861193712&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2012.02.004
DO - 10.1016/j.jaut.2012.02.004
M3 - Article
C2 - 22459490
AN - SCOPUS:84861193712
SN - 0896-8411
VL - 38
SP - 344
EP - 353
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
IS - 4
ER -