As we were discussing in class about the immune system’s inefficacy as we age, I remembered recently coming across an article in the U.S. News
Health section that suggested build-up of a particular protein, dual specific
phosphatase 6 (DUSP6), is a cause in lack of response to vaccines in the older
population. Below are the links to the article from U.S. News and Dr. Goronzy’s
research article published in Nature Medicine for those who are interested in
reading the full article(s).
Summary: Goronzy and his laboratory noted that there was a
defect in t-cell receptor-induced phosphorylation of ERK in naïve CD4(+) cells,
these are t-cells that have yet to meet their antigen. After investigating what attributed to this
defect they found as people age people have increasing levels of DUSP6 due to decreasing levels of miR181a, a
DUSP6 repressor[2]. The dysregulation of this pathway, particularly the
decreased ERK signaling, decreased the ability of naïve cell activation in reaction
to antigens [1,2]. After reintroduction miR181a or a DUSP6 inhibitor, they detected
increased proliferation, increased expression of activation markers, and supported preferential T helper type 1
cell differentiation, all signs of an activated t-cell. They conclude
that DUSP6 could be a potential target to increase the immune response to
vaccines in the older population.
Notes: CD4 is a transmembrane
glycoprotein that stabilizes t-cell receptor’s (TCR) interaction with antigen
presenting cells. T-cells are typically divided between CD8(+), cytotoxic t-cells, and CD4(+), t-cells binding with antigen presenting cells and binding/activating B-cells (I think). DUSP6 is a phosphatase, meaning it de-phosphorylates proteins
at tyrosines/serines/threonines.
My thoughts: ERK is activated through
phosphorylation. Logically thinking, build-up of a phosphatase (such as DUSP6) that
could target ERK or any of the kinases with in the cascade could lead to abrogate activation of the naïve t-cell. Although I am not yet highly knowledgeable
about t-cell activation, I find Goronzy’s discovery incredible; if it works.
References
(1) Koike T, et al. A Novel ERK-dependent Signaling
Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell
Activation. The
Journal of Biological Chemistry. 278;15685-15692, 2003.
(2)
Li G, et al. Decline in
miR-181a expression with age impairs T cell receptor sensitivity by increasing
DUSP6 activity. Nature Medicine.
Published online Sept 30 2012.
This is an amazing finding that DUSP6 inhibition could possibly increase older individual’s immune response. I was interested to see if other dual specific phosphotases are involved with the immune response since they have a profound role in regulating many pathways in the cell. I found from my research that DUSP4 and DUSP5 have been found to play important roles in the immune response in older individuals. DUSP 4 has been found to be unregulated in older individuals CD4 memory T cells. This causes the memory t-cell to not be able to differentiate into T-helper cells, which we learned in class are important for B cells response to antigens.
ReplyDeleteDUSP4, 5, and 6 are unregulated in older individuals CD8(+) T cells. CD8(+) T cells are involved in our body’s protection against viruses and surveillance for cancer cells. All three of these dual specific phosphatases play a role in regulating ERK1 and ERK2. ERK1/2 is part of the RAS-MAPK pathway which leads to T-cell activation and proliferation. I think that DUSP5 or DUSP4 could also be potential pharmaceutical targets to increase the immune response in older individuals.
Sources:
http://www.globe-network.org/documents/conferences/2012/aging-and-immunity-2/programme.pdf
http://www.pnas.org/content/early/2012/03/20/1109797109.full.pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00534.x/full
To continue on the discussion of the drug targeting idea. I feel pathways such as this have multiple components and enzymes which serve in regulation. Treatment options should take this into account, since the problem may not necessarily be DUSP6 in everyone, it could be DUSP4 or 5. Furthermore, a treatment could consider multiple targets as well. This is similar to the case with insulin resistance and serine kinases which deactivate the insulin receptor and IRS-1. Therefore, I think treatment options are a long ways, but this is a very good start. Overall, I thought this was a pretty cool article.
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