Overexpression of a mutant CTLA4 inhibits T-cell activation and homeostasis-driven expansion.
OBJECTIVE
Interaction of B7 with CD28 and CTLA4 plays an important function in T-cell activation and homeostasis. Disruption of CD28, CTLA4, or both has shown impact on T-cell biology. This paper examined the consequences of overexpressing a tailless mutant form of CTLA4 on T-cell activation and in vivo expansion.


METHODS
Retroviral gene transfer was used to infect bone marrow progenitor cells with either a control vector or a cytoplasmic domain-deleted mutant of CTLA-4 (deltaCTLA4). The cells were subsequently adoptively transferred to RAG-/- mice and allowed to repopulate. The T cells derived from the reconstituted RAG-/- mice were analyzed functionally in vitro and in vivo.


RESULTS
The T cells were defective in their ability for IL-2 secretion, survival, and proliferation in response to Ag/APC stimulation in vitro. Addition of exogenous IL-2 or normal T cells was able to rescue the survival defect and allow cell-cycle progression. In adoptive transfer studies, the naïve T cells expressing deltaCTLA4 exhibited compromised capability to expand in RAG-/- mice. Memory deltaCTLA4T cells, however, were capable of proliferating in lymphopenic hosts to a similar extent as control memory T cells, but showed reduced survival.


CONCLUSIONS
Surface deltaCTLA4 has similar tolerogenic/regulatory activity as CTLA4-Ig. In contrast to CTLA4-Ig, the effect of deltaCTLA-4 is autonomous. The inhibition of in vivo expansion by deltaCTLA4 indicates developmental and/or activation stage dependency of costimulation in T cells.
Genencor International, Inc., Palo Alto, CA 94304, USA.
Yifan
Y
Mao
Dan
D
Brigham
Dan
D
Chen
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D060908:CTLA-4 Antigen; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology; D006706:Homeostasis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020800:Receptor, Nerve Growth Factor / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D007376:Interleukin-2; C499308:Rag2 protein, mouse; D020800:Receptor, Nerve Growth Factor; C064655:V(D)J recombination activating protein 2