Research: CD8 Cells can be Good and Bad

R
EpubMangalam 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.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

1 comment

  • Would a viral hypothesis potentially explain relapses in RRMS? For instance, could there be "viral blooms" which would mark the beginning of a relapse?

    Are there lots of known things that could explain the relapsing nature of RRMS or almost none?

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