Human Anatomy, Physiology, and Medicine. Anything human!
I m new to this website and have found it very informative however i have one question I could not find the answer to (probably because it's just common sense!) but anyway here it is:
Where does the differentiation of T cells take place?
As i understand it when the t cell is activated in the lymph nodes it differentiates into Th and Tc. Tc go off to the inflamed tissue and Th cells diferentiate into Th1 and Th2 and the Th2 migrate to the B cell follicle to activate B cells, while other Th2 and Th1 cells go to the tissuses.
However I think it might be that the Th cells migrate to the extralymphoid tissues and differentiate there?
Could someone please help clarify it for me?
Thanks for the quick reply!
However there is one thing which is still confusing me, if they differentiate in the lymph then how are the cytokines which favour one differentiation or another delivered. It's just that in my notes it says NK cells and macrophages can have an effect on the type of Th produced
I cant seem to picture it because ive read they are differentiated in the tissues but have also read that once activated Th1 and Th2 home to different types of infection
Thanks again for the quick reply
So after they have been activated in the lymph nodes they travel to the thymus where they differentiate and then migrate to infected tissue
If anyone knows of a source which provides a good overview of this please let me know. I dont want to sound lazy because I have looked around a lot of places and everywhere describes the processes on their own, like t/APC interactions and th differentiation wiothout linking where they happen and how they move around
There are differen stages of differentiation. For CD4+ cells, for example, there are so-called recent thymic emigrants (RTE, yeah sounds stupid I know :P), T cells that have emerged from the thymus after their T cell receptor has been deemed appropriate (e.g. it does not recognize self molecules with high affinity, but recognizes foreign ones sufficiently). RTEs are naive T cells in a sense that they are yet to encounter their specific antigen in the periphery. Furthermore, they are not yet deviated into any T helper or T effector subtype.
What exactly determines the final outcome of the T cell phenotype is still unclear, but it seems it involves regulatory T cells, APC signals, cytokines and T cell receptor affinity among other things. The initial development, though, takes place in the thymus (like mentioned above), which determines e.g. the CD4+/CD8+ and A:B/G:D TCR development. The final adjustment, then, happens in the periphery (such as lymph nodes).
Apparently RTEs are a relaively recent finding, with Haines et al. (2009) describing a protocol to indentify them, but for a good overall picture I suggest you try to get your hands on Janeway's Immunobology 7th ed. by Murphy, Travers & Walport.
edit: Interestingly, the removal of thymus in adult age results in no apparent loss of T cell function or numbers, which suggests that after puberty the T cell pool is large enough to cover the epitopes they need to recognize, and that the cells are both long lived and divide in the periphery. Thus, in adults, the immune system seems to be able to carry out the crucial parts of T cell differentiation outside the thymus. Naturally there is no thymic selection in this scenario, but there is also no production of new T cells "from scratch".
Thanks for the comprehensive reply biohazard and the extra bit of info. It's certainly expalined alot but i would just like clarify so the differentiation into subsets can be done in several peripheral tissues including at the site of infection?
Yes, the final stages of lymphocyte differentiation take place in the peripheral tissues.
Often this peripheral tissue is a secondary lymphoid tissue, such as a lymph node, but also circulating naive CD45RA+ lymphocytes in the blood or at the site of infection switch to CD45RO+ memory phenotype if they encounter their specific MHC:peptide complex. Depending on the TCR signaling, prevaling cytokine environment, and cell-cell interactions, the memory cells can be divided to central memory cells or effector memory cells, which in turn can acquire a Th1, Th2, or Th17 effector phenotype.
Thanks for the explanation biohazard. I think i've got it now: The T cells are produced in the thymus as naive CD4+ and CD8+ cells and then recognise the antigen in the lymph nodes (mainly) but recently there have been RTE's discovered which are not yet CD4 or CD8 positive and differentiate upon activation
Well, you almost got it :)
RTEs already express CD4 or CD8 marker (all T cells leaving the thymus are "single positive" CD4+ or CD8+ cells, although these include a small subset of CD4+ regulatory T cells). However, there are some other differences that separate RTEs from "normal" naive T cells. RTEs mature into normal naive cells, and after antigen recognition they divide and gain their effector function (and switch from CD45RA+ to CD45RO+ among some other changes).
T cells regularly circulate between lymphatic tissues and blood, so they have plenty of chances to encounter their antigen (presented by APCs such as dendritic cells) or excert their effector function (e.g. to induce antibody production by B cells [CD4+ helper cells] or kill infected cells directly [CD8+ cytotoxic cells])
I don't have the RTE paper at hand at the moment, but I can check what made RTEs different from naive T cells when I get back to work and have some time. I don't know how important it is to know that there is this phase in the T cell cell life, but I pointed it out mostly to indicate that there indeed are several differentation events that take place in the pheriphery - just like you suspected.
edit: RTEs can be distinguished from normal naive CD4+ cells primarily by their protein tyrosine kinase 7 expression, and they are less responsive and have poor effector function. So, does knowing this have any practical significance? The authors write:
"This immaturity in CD4+ RTE effector function may contribute to the reduced CD4+ T cell immunity observed in contexts in which CD4+ RTEs predominate, such as in the fetus and neonate or after immune reconstitution. The ability to identify viable CD4+ RTEs by PTK7 staining should be useful for monitoring thymic output in both healthy individuals and in patients with genetic or acquired CD4+ T cell immunodeficiencies." (Haines et al. 2009)
I am looking for some basic information about differentiation in general. And T-cell differentiation is a great system. Since the thread is in, thought of posting this question here.
Do cells actively divide during the differentiation process? I mean, when a progenitor cell is activated (by antigen or some other stimuli), do they keep dividing during the various stages of differentiation?
I would appreciate help on this. If you know of any good review, I would love to check it out.
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