Antigen-specific T-T interactions regulate CD4 T-cell expansion

Abstract

The regulation of CD4 T-cell numbers during an immune response should take account of the amount of antigen (Ag), the initial frequency of Ag-specific T cells, the mix of naive versus experienced cells, and (ideally) the diversity of the repertoire. Here we describe a novel mechanism of T-cell regulation that potentially deals with all of these parameters. We IntroductionBecause the frequency of T cells specific for any antigen (Ag) is low, T-cell proliferation is an important part of primary immune responses. However, proliferation must stop at some point to allow Ag-specific T cells to become effectors (and to accommodate a limited body size). In a typical primary immune response, CD4 T cells proliferate extensively and generate effector cells before a contraction phase sets in. The extent of proliferation depends upon the initial frequency of the Ag-specific T cells and is therefore much greater for naive T cells than for the more numerous memory T cells. [1][2][3] Because memory and naive cells reach the same plateau, even though memory cells respond faster, there must be mechanisms that regulate T-cell proliferation early during an immune response. 4,5 It has been suggested that T-cell proliferation is related to the disappearance of Ag or antigen-presenting cells (APCs), [6][7][8] to exhaustion of the APCs, 9 to suppression by regulatory T cells, 10 or to competition among responding T cells. [11][12][13][14] However, disappearance or exhaustion of APCs should generate higher final plateaus for the fasterresponding memory T cells; and pure competition for waning Ag would rapidly lead to preferential expansion of high-avidity T-cell clones, and thus to a narrowing of the repertoire. This is not observed for CD4 T-cell responses, where the avidity range remains quite wide. 15 While studying regulation of a localized CD4 immune response, we found yet another mechanism. Responding CD4 T cells capture and present their cognate MHC/Ag complexes in a manner that is strongly inhibitory for activated/memory CD4 T cells but not for naive T cells. This inhibition regulates the intensity of the immune response in relation to the amount of presented Ag while keeping the repertoire diverse, as new naive T cells can still enter the immune response. Methods MiceMarilyn TCR-transgenic Rag2 Ϫ/Ϫ mice are specific for the Dby-H-Y male antigen presented by A b . 16 For Marilyn T cells expressing diphtheria toxin receptor (DTR), we crossed Marilyn Rag2 Ϫ/Ϫ CD45.1 mice to Lat-DTR knockin mice (harboring, in the 3Ј untranslated region of the Lat gene, 17 a human diphtheria toxin receptor (DTR) cassette, driven by an internal ribosomal entry site [A.K. and B.M., manuscript in preparation]) to finally obtain Marilyn-Lat-DTR.Rag2 Ϫ/Ϫ .CD45.1/2 mice. B6-OT-II 18 and B6 mice were from CRL (Charles River Laboratories, L'Arbresle, France). Live animal experiments were done according to French Veterinary Department guidelines. Cell preparationEffector and memory T cells were generated in vivo as described, 19 by transferring 10 6 Marily...

Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

“…The long lifespan of MHC-II-restricted Ag presentation we observed is consistent with our previous data using peptide-loaded LPS-matured DCs that induced proliferation of naive CD4 + T cells for more than 3 wk (19). A high stability of the MHC-II peptide complexes is indeed a common feature of immune-dominant MHC-II epitopes (20).…”

“…One way to avoid this caveat is to wait a few days after tumor cell seeding before transferring naive tumor Ag-specific T cells. Nonetheless, although this might allow the study of the CD8 + T cell response as the MHC-I:peptide complexes are short lived, this is not sufficient for CD4 + T cells because the lifespan of MHC-II: peptide complexes can be above 3 wk (19,20) as we will also show in this study in a tumor context. To overcome this difficulty, a cell line expressing a MHC-I epitope fused to GFP at low level could be induced to high expression upon in vitro Cre-LoxPmediated recombination (21).…”

“…The high number of intermediary divided (1-4) cells (Fig. 3C) could represent continuous recruitment of naive T cells or, alternatively, arrest of T cell proliferation by T-T interactions as described previously (19). To distinguish these two hypotheses, we injected BrdU for 5 d before harvesting the TdLN 15 d after T cell transfer (Fig.…”

Presentation of Acquired Peptide-MHC Class II Ligands by CD4+ Regulatory T Cells or Helper Cells Differentially Regulates Antigen-Specific CD4+ T Cell Response

“…In contrast, these acquired ligands may serve as a regulatory mechanism to modulate immune response by making the host cells susceptible to apoptosis or CTL killing (10,11). Furthermore, Ag presentation by CD4 + T cells can induce anergy and apoptosis in responding T cells (10,12,13). Of particular interest, specialized regulatory T cells (Tregs), including induced Tr1 cells (14) and CD4 2 CD8 2 CD3 + double-negative Tregs (15), have been shown to be able to use acquired peptide-MHC-I ligands to target Ag-specific CD8 + T cells and subsequently suppress their activation and function.…”

CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity

“…20,21 Surface molecule transfer has been predominantly reported for the transfer of DC surface molecules to T cells in a unidirectional manner. 22,23 As a result, T cells with acquired DC molecules have been shown to be either immunogenic 12,24 or tolerogenic 25,26 in their effect on immune responses. In addition, T cells with uptake of DC-released EXO have been used as T-cell vaccines for stimulation of antitumor immunity.…”