CD8 lethargy in the absence of CD4 help

Abstract

CD4 T cell help was proposed to have a pivotal role in orienting CD8 T cell responses to antigen stimulation. By activating antigen‐presenting cells (APC), CD4 cells would induce their expression of costimulatory molecules, the "signal two" required to induce full CD8 activation, preventing CD8 tolerance. Recent data on this subject is contradictory, as the absence of help did not alwaysresult in CD8 tolerance. These differences were attributed either to the presence of residual CD4 help or, respectively to the type of antigen stimulation, the peptide affinity, the CTL frequencies, and/or the strength of the response. We therefore reassessed the role of CD4 help in CD8 responses using a system where CD4 cells are absent and APC not activated. This system can be manipulated to induce CD8 tolerance (at high antigen concentrations) or CD8 memory (at low antigen concentrations). We found that the presence of CD4 help did not prevent tolerance induction. On the other hand, the absence of CD4 help did not induce CD8 tolerance, but rather led to differentiation stage intermediate between naive/memory/tolerant cells that we call "lethargy". These findings indicate that role of CD4 help in CD8 responses does not follow a simple on‐off rule, as previously suggested. They also reveal that the "tolerance versus memory" dichotomy fails to account for all possible states/properties of antigen‐experienced CD8 cells. Depending on the priming conditions, other intermediate stages of differentiation may occur.

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

“…8,9 It was demonstrated both in viral infection and tumor models that CD4 þ T cells support CD8 þ T cells for full activation by providing costimulatory signals and necessary cytokines. [32][33][34][35] Nonetheless, a concern on the use of PBLs may arise because a portion of CD4 þ T cells exerts Th2 response. However, a number of studies demonstrated that the antigen-specific support from both Th1 and Th2 cells is also critical when CD8 þ T cells are rechallenged for memory responses.…”

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

“…Maintenance of memory CD4 and CD8 cells seems to be independent of antigen or MHC class II and I molecules, respectively [20,21]. The generation of efficient CD8 memory T cells requires the presence of CD4 T cells [22][23][24][25]. Longevity of memory T cells appears to be cytokine driven.…”

Immunogenicity and Safety of a Booster Dose of an Investigational Adjuvanted Polyprotein HIV-1 Vaccine in Healthy Adults and Effect of Administration of Chloroquine

“…While CD8 ϩ T cells are known to be an important immune effector mechanism for the elimination of HIV-infected cells, it is increasingly apparent that CD4 ϩ T cells provide essential help to other components of the adaptive immune response and are also crucial for the induction of effective HIV immunity (5-7). In particular, CD4 ϩ T cells appear to play an important role in maintaining functional CD8 ϩ T-cell responses (8)(9)(10)(11)(12)(13)(14)(15).…”