APC targeted Ag: can it direct Th1 or Th2 responses

R M Bernstein ralph at ccit.arizona.edu
Wed Oct 4 17:44:24 EST 1995

In Article <M_Doherty-0909561420550001 at db425.niaid.nih.gov>,
M_Doherty at NIH.gov (M. Doherty) wrote:
>In article <ralph.1163043724A at>, ralph at ccit.arizona.edu (R M
>Bernstein) wrote:


>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

I was thinking along the lines of "

    Kuchroo VK.  Das MP.  Brown JA.  Ranger AM.  Zamvil SS.  Sobel RA.  Weiner *
    HL.  Nabavi N.  Glimcher LH.                                               *
   Institution                                                                 *
    Department of Neurology, Harvard Medical School, Boston, Massachusetts     *
    02115.                                                                     *
   Title                                                                       *
    B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2  *
    developmental pathways: application to autoimmune disease therapy.         *
   Source                                                                      *
    Cell.  80(5):707-18, 1995 Mar 10.                                          *
   MeSH Subject Headings                  

This immediately made me consider if b71 b72 could then be used as markers. 
If they are on the cells that they stimulate, then they would conceivable
stay expressed on those cells while expressing a th1 th2 phenotype.  Any ideas?

Regards, Ralph

Ralph M. Bernstein
Dept of Micro/Immuno
University of Arizona
Ph: 602 626 2585
Fx: 602 626 2100
url: http://lamprey.medmicro.arizona.edu

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