Costimulatory blockade induces hyporesponsiveness in T cells that recognize alloantigen via indirect antigen presentation.
BACKGROUND
Blockade of T cell costimulation by treatment with donor-specific transfusion (DST) and anti-CD154 monoclonal antibody (mAb) induces prolonged allograft survival in mice. This effect is due in part to deletion of host CD8 and CD4 T cells that recognize alloantigen by direct presentation. The fate of host CD4 T cells that recognize alloantigen by indirect presentation, however, is unclear.


METHODS
We studied Tg361 TCR transgenic CD4 T cells that recognize alloantigen by indirect presentation. Carboxyfluorescein diacetate, succinimidyl ester-labeled Tg361 cells were adoptively transferred into syngeneic nontransgenic recipients and their fate in the peripheral blood, spleen, and lymph nodes following treatment with DST and anti-CD154 was analyzed.


RESULTS
Treatment of mice with DST plus anti-CD154 mAb does not delete Tg361 CD4 T cells, but instead renders them hyporesponsive to rechallenge with alloantigen. Mice circulating hyporesponsive CD4 T cells also fail to reject skin allografts. The hyporesponsive state of the T cells is not reversed by the addition of interleukin-2, anti-CD28 mAb, or an agonistic anti-CD134 mAb in the presence of antigen. These T cells are capable of activation, however, as evidenced by in vitro proliferation in response to anti-CD3 mAb.


CONCLUSIONS
These results demonstrate that costimulation blockade can induce hyporesponsiveness of host CD4 T cells recognizing alloantigens by indirect presentation, thus prolonging graft survival by a mechanism that does not involve deletion of alloreactive T cells.
Phillips
Nancy E
NE
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. nancy.phillips@umassmed.edu
Greiner
Dale L
DL
Mordes
John P
JP
Rossini
Aldo A
AA
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D023201:CD40 Ligand / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D006224:Cricetinae; D005452:Fluoresceins / Q000494:pharmacology; D006085:Graft Survival; D007108:Immune Tolerance; D007519:Isoantigens / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology*
D005452:Fluoresceins; D007519:Isoantigens; C027780:carboxyfluoresceindiacetate; D023201:CD40 Ligand