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Abstract
We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII)-binding peptide of hen egg lysozyme (HEL) is facilitated when mice are immunized with splenic antigen presenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs), can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252) interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of “epitope-spreading” seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.
Highlights
Cooperation between lymphocytes is essential for the induction of most immune responses
Differences in antigen processing and their availability within different physiological niches are other properties that set dendritic cells (DCs) and B cells apart as antigen presenting cells (APC).In order to take our analysis of CD4 T cell cooperation further, we have developed a simple in vivo approach where mice are given APC pulsed with one major histocompatibility class-II (MHCII) binding peptide or with this peptide and another that binds to a different host MHCII molecule
In order to explore the mechanism whereby CD4 T cells specific for one peptide could help the generation of CD4 T cells specific for another peptide, we developed a system where we could control the type of APC presenting the two peptides
Summary
Cooperation between lymphocytes is essential for the induction of most immune responses. Knowledge of the circumstances leading to the optimal activation of CD4 T cells is critical to understanding how robust immune responses are generated. We [9,10,11], and others [12,13], have provided indirect evidence that the optimal activation of CD4 T cells requires lymphocyte cooperation in the form of CD4 T cell collaboration. Gerloni et al reported that mice immunized with a DNA vector encoding a polypeptide generated a greater CD4 T cell response if the vector encoded an immunodominant peptide recognized by other CD4 T cells [12]. Creusot et al reported that cooperation between two T cell receptor (TCR)transgenic CD4 T cell populations occurred in mice in response to vaccination with DNA vectors encoding separate polypeptides [13]; cooperation was most efficient when the two vectors were delivered to the same cell. We showed in BALB/c mice that the in vivo generation of CD4 T cells specific for minor peptides of the antigen hen egg lysozyme (HEL) is facilitated by CD4 T cellsspecific for the immunodominant peptide, HEL105–120 [11]
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