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International Immunology, Vol. 13, No. 4, 441-450, April 2001
© 2001 Japanese Society for Immunology

Multiple co-stimulatory signals are required for triggering proliferation of T cells from human secondary lymphoid tissue

Samir G. Agrawal1,4,6, Jeanine Marquet1,4, Joël Plumas5, Hélène Rouard1, Marie-Hélène Delfau-Larue1, Philippe Gaulard2, Laurence Boumsell4, Félix Reyes3, Armand Bensussan4 and Jean-Pierre Farcet1,4

1 Departments of Immunology,
2 Histopathology and
3 Clinical Hematology, and
4 INSERM Research Unit U448, Henri Mondor Hospital, 94010 Créteil, France
5 Immunology Department, ETS Isère-Savoie, BGMT UA 2021, 38701 Grenoble, France

Correspondence to: J.-P. Farcet, Laboratoire d'Immunologie Biologique, Hôpital Henri Mondor, 94010 Créteil, France

Vaccine-based therapies are being developed for a variety of cancers and their efficacy will be determined by their ability to stimulate T cells in the secondary lymphoid tissue. We found that T cells isolated from human secondary lymphoid organs (LT-T), in contrast to peripheral blood T cells (PB-T) are hyporesponsive to cross-linked anti-CD3 mAb (CD3c) even in the presence of exogenous IL-2. Using mAb to trigger CD2 and CD28 co-stimulatory molecules, we found that such dual co-stimulation of LT-T induces profound and sustained responses including CD25 expression, IL-2 secretion and proliferation. Different levels of co-stimulation produced a hierarchical pattern of responses in LT-T, which correlated with the degree of CD3–TCR down-regulation. Mature antigen-presenting cells (APC) restored the capacity of LT-T to proliferate to stimulation of the CD3–TCR complex. Blocking studies demonstrated that optimal proliferation was critically dependent on co-stimulation via CD2 and CD28 engaged by their ligands on the APC. Therefore, LT-T have increased co-stimulatory requirements as compared to PB-T, i.e. multiple co-stimulatory signals coupled to CD3–TCR triggering. Furthermore, LT-T were found to be dependent on APC for survival, in contrast to PB-T. Clearly, LT-T do not behave in a comparable way to PB-T and in vitro experiments assessing novel cancer vaccines should therefore use LT-T as the most appropriate population of responder T cells.

Keywords: anergy, antigen-presenting cell, anti-tumor vaccination, CD2, CD3–TCR down-modulation, CD28, lymph node, non-Hodgkin's lymphoma

6 Present address: Department of Haematology, Southampton General Hospital, Southampton SO16 6YD, UK

Transmitting editor: J. F. Bach


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