Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Abstract

Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

Transient stimulation expands superior antitumor T cells for adoptive therapy

“…Furthermore, our data suggest that the duration of T cell stimulation for optimal T cell expansion was different between CD4 + and CD8 + T cells and that CD4 + T cells required more prolonged stimulation than CD8 + T cells. These observations are consistent with recent mouse studies; CD8 + T cells were able to proliferate and differentiate into effector T cells in response to transient antigen presentation, while CD4 + T cells required sustained antigen exposure for continued growth (37,38).…”

Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory

“…Some studies suggest that effector CD4 T cell division is programmed by initial Ag encounter (33, 34), while others suggest that CD4 T cells do not undergo such “autopilot” proliferation after 2 d of stimulation during priming (10), but it remains unclear if they acquire this ability later during infection. To determine if division past 6 dpi depends on Ag recognition, we labeled isolated 6 dpi effectors with CFSE, transferred to hosts with and without Ag, and assayed dilution of dye at 3 dpt.…”

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

“…MOR209/ES414's design enables efficient induction of target-dependent cell lysis and T-cell proliferation over multiple days in the presence of only moderate levels of cytokine release when PSMA target is present. After exposure to MOR209/ ES414, CD8 þ T cells showed robust target-dependent proliferation, but a reduced degree of proliferation was seen from CD4 þ T cells, which are predominantly responsible for cytokine production (27). The resulting limited cytokine release could arise from the structure of the ADAPTIR format, which may attenuate the degree of TCR stimulation compared with other bispecific antibody formats.…”