APC targeted Ag: can it direct Th1 or Th2 responses

M. Doherty M_Doherty at NIH.gov
Tue Oct 3 13:32:54 EST 1995

In article <ralph.1163043724A at>, ralph at ccit.arizona.edu (R M
Bernstein) wrote:

> In Article <Pine.HPP.3.91.951001211734.10202A-100000 at fhs.csu.McMaster.CA>,
> Denis Snider <sniderd at fhs.csu.McMaster.CA> wrote:
> >On 28 Sep 1995, William F. Wade wrote:
> >> What evidence is there, if any, that targeting antigen to a specific
> >> internalization pathway or APC type favors a Th1 vs Th2-type response. >
> >William,
> >        I've been doing studies on antigen targetting in vitro and in 
> >vivo for the last few years.  I have seen nothing in the literature that 
> >answers your question directly.  So far as is known now, Th1 and Th2 are 
> >more determined by the nature of the cytokine microenviroment available 
> >during the initial response of the naive Th precursor.  For instance 
> >IL-12 and IFN-gamma promote Th1 and IL-4 promotes Th2.  However, it is 
> >known that the best APC for proper activation of Th precursors is the 
> >dendritic cell or an activated B cell.  That is from in vitro (no in 
> >direct in vivo evidence yet) work by among others Drs. S.Swain, T. 
> >Mossman, Seder, and others, published mostly in JI, JEM, etc/ 
> >
> >        Good luck.  Let me know if you find more useful information.
> >
> >Denis Snider   PhD

> related to this topic,
> has anyone seen anymore data on the ability of b71 and b72 to serve as
> markers to determine the th1 / th2 commitment of t cells?
> regards, ralph
> Ralph M. Bernstein

Well there is a little more evidence about than that, but it's still an
open question.  In vitro work indicated that macrophages were better APC
for Th1 development (1, 2) and we demonstrated that this could also be
shown of some macrophage types in vivo, in either antigen or infection
models (3, 4).  Recent work (no publication, I'm still doing the writing
:)) suggests that differential production of cytokines by APC -
specifically IL-12 and TGF-b are the cause.  APC (or at least macrophages,
which is all I can write on with any pretense to authority) seem pretty
homgenous as regards cytokines.

There is also some suggestion that the concentration of antigen presented
can affect T cell subset development, and since levels of class II MHC can
vary wildly between different APC, this could affect the outcome.  Kim
Bottomly has written a bit on this over the last few years and there is
some nice new evidence from transgenic models to support it.  I can't call
up the papers off the top of my head, but some of the people doing the
work are Stephanie Constant, Nancy Hoskens and Barbara Fazekas de St.

The basic line of thinking is that Th2 cells are less susceptible to being
turned OFF by inappropriate stimulation than Th1 cells, so that if antigen
is low or too high, then they will  have the advantage.  Since Ag-specific
B cells can acquire antigen at high efficiency via their specific
receptors and DC have more class II and costimulatory molecules, these
cells would have an advantage in presenting Ag at low concentrations,
which may lead to their being predominantly associated with Th2 responses.

Finally as regards B7.1 and B7.2, Laurie Glimcher has published data in J.
Exp. Med (sorry can't remember exact issue/title) supporting differential
effects on TH1/2 development, and Rich Locksley's group drew similar
conclusions from a mouse infection model (5).  This is still very
contoversial as other groups have results which don't agrre with the in
vitro data published, and Rich's work can be interpreted in other ways. 
My personal bias (which I reserve the right to change at any time!) is
that it may play a minor role, all other factors being equal, due to the
ability of these factors to increase the intensity of the signals.

1.  Gajewski, T. F., M. Pinnas, T. Wong and F. W. Fitch.  1991.  Murine
Th1 and Th2 clones proliferate optimally in response to distinct
antigen-presenting cell populations.  J Immunol  146:1750.
2.   Gajewski, T. F., S. R. Schell, G. Nau and F. W. Fitch.  1989. 
Regulation of T-cell activation: differences among T-cell subsets. 
Immunol Rev  111:79.
3.   Doherty, T. M. and R. L. Coffman.  1993.  Leishmania antigens
presented by GM-CSF-derived macrophages protect susceptible mice against
challenge with Leishmania major.  J Immunol  150:5476.
4.   Doherty, T. M., S. G. Love, D. R. Harding and J. D. Watson.  1994. 
Reversal of T cell unresponsiveness by augmentation of antigen presenting
cell function.  Int Immunol  6:761.
5.   Corry DB, Reiner SL, Linsley PS, Locksley RM: Differential effects of
blockade of CD28-B7 on the development of Th1 or Th2 effector cells in
experimental leishmaniasis. J Immunol 1994, 153:4142-8.

OK, if you've read this far and are still interested, I feel I should also
mention Erwin Rude's group, who did a lot of early work on the effect of
macrophage factors on T cell development in vitro.

Hope this sheds light rather than obscurity!

Cheers, Mark Doherty
Fogarty Fellow

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