Epub: Mangalam et al. Two discreet subsets of CD8 T cells modulate PLP(91-110) induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice. J Autoimmun. 2012 Mar 27.
Previously
these investigators showed that transgenic, or designer, or Frankenstein, mice expressing a human gene, called HLA-DR3, are
susceptible to experimental autoimmune
encephalomyelitis (EAE) (mouse MS). The EAE in these mice was induced by vaccinating these mice with the autoantigen PLP(91-110). PLP is part of the proteolipid protein which is a structural protein found in myelin; the fatty insulation around nerves that allows nerve to conduct electrical impulses very quickly and efficiently (low energy).
These HLA-DR3 mice with EAE showed increased number of a type of white blood cell referred to as CD8 T
cells indicating these cells are important role in EAE.
The role
of CD8 T cells in MS has
been enigmatic as it has been assigned both regulatory and pathogenic
roles.
Therefore, to evaluate the role of CD8 T cells, they generated CD8
deficient HLA-DR3 transgenic mice (DR3.CD8(-/-); double-designer or Frankenstein-Frankenstein mice.
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.
The researchers then showed that two subsets of CD8 T cells can be differentiated
based on the surface expression an immune molecule called CD122 (IL-2 Rβ chain). Wow this is getting complicated! In short these cells can either have this molecule (CD8+CD122+) or they don't have this molecule (CD8+CD122-).
"I assume you can see how the nomenclature works."
CD8 T cells
expressing CD122 (CD8+CD122+) play a regulatory (anti-inflammatory) role while CD8+CD122- T
cells act as a pathogenic or inflammatory 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.
"To understand this post you need to have done a course in immunology; apologies."
They also showed that adoptive transfer of CD8CD122- T cells (this is when the cells are taken from one animal and infused into another animal) caused increased spinal cord demyelination indicating that these are
pathogenic subset of CD8 T cells.
This 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.
"Interestingly CD8+ T-cells predominate in the centre of active MS lesions. CD8+ T cells are the ones that target viruses, which is one reason why I am so enthralled by the viral hypothesis."
"The major HLA-D variant associated with MS is the DR2 variant and sometimes the DR4 variant. In this genetically-modified variant, expressing human DR3, the mice get a lot of CD8 cells in their CNS when they develop an MS-like disease. They investigators find two roles for the CD8+ cells in this model; (1) a regulatory of anti-inflammatory role and (2) a pathogenic or inflammatory role. It is not surprising that CD8+ cells may have dual functions; in the past there were referred to as suppressor/cytotoxic cells (cytotoxic means killing cells). However this means the presence of CD8+ cells, such as a cell that reacts against EBV, does not tell us whether it is a damaging cell or a regulatory cell. Regulatory CD8+ cells in the presence of a virus could be bad as it would potentially allow the infection to spread."
"I know most of you will have problems understanding this post; it does however give you some idea how complex immunology is and the types of studies MouseDoctors do to unravel the mysteries of the immune system in relation to MS."