Direct demonstration of CD4 T cell cooperation in the primary in vivo generation of CD4 T effector T cells

Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
International Immunology (Impact Factor: 2.54). 04/2012; 24(8):519-27. DOI: 10.1093/intimm/dxs055
Source: PubMed


Many observations bear upon the cellular and molecular requirements for CD4 T cell activation. The interaction of CD4 T cells
with dendritic cells (DC), central to the induction of most immune responses, is the most studied. However, leukocytes other
than DC can dramatically affect the induction and differentiation of CD4 T cells into effector cells. We recently provided
indirect evidence that in vivo CD4 T cooperation facilitates the activation of CD4 T cells. Here, we demonstrate that the activation of CD4 T cells, specific
for the hen egg lysozyme (HEL)105
–120 peptide, is optimally achieved when BALB/c mice are immunized with additional MHC class II-binding HEL peptides in incomplete
Freund’s adjuvant. This cooperation cannot be mimicked by the coadministration of LPS or of an agonistic antibody to CD40,
at the time of immunization. In contrast, OX40–OX40L interactions are necessary for CD4 T cell cooperation in that an OX40
agonistic antibody can replace, and an OX40L-blocking antibody can abrogate, CD4 T cell cooperation in situations where such
cooperation would otherwise enhance the activation of CD4 T cells.

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Available from: David R Kroeger, Aug 25, 2015
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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.
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    ABSTRACT: The establishment of central tolerance to most self-antigens results in a repertoire of mature, peripheral lymphocytes specific for foreign and peripheral self-antigens. The framework that single, mature lymphocytes are inactivated by antigen, whereas their activation requires lymphocyte cooperation, accounts for diverse observations and incorporates a mechanism of peripheral tolerance. This framework accounts for the generalizations that the sustained activation by antigen of most B cells and CD8 T cells requires CD4 T helper cells; in the absence of CD4 T cells antigen can inactivate these B cells and CD8 T cells. In this sense, CD4 T cells are the guardians of the fate of most B cells and CD8 T cells when they encounter antigen. I argue here that the single lymphocyte/multiple lymphocyte framework for the inactivation/activation of lymphocytes also applies to CD4 T cells. I consider within this framework a model for the activation/inactivation of CD4 T cells that is consistent with the large majority of contemporary observations, including significant clinical observations. I outline the grounds why I feel this model is more plausible than the contemporary and predominant Pathogen- Associated-Molecular-Pattern (PAMP) and Danger Models for CD4 T cell activation. These models are based upon what I consider the radical premise that self-nonself discrimination does not exist at the level of mature CD4 T cells. I explain why I feel this feature renders the PAMP and Danger Models somewhat implausible. The model I propose, in contrast, is conservative in that it embodies such a process of self-nonself discrimination.This article is protected by copyright. All rights reserved.
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