APCs Expressing High Levels of Programmed Death Ligand 2 Sustain the Development of CD4 T Cell Memory

Abstract

The role APCs play in the transition of T cells from effector to memory remains largely undefined. This is likely due to the low frequency at which long-lived T cells arise, which hinders analysis of the events involved in memory development. In this study, we used TCR transgenic T cells to increase the frequency of long-lived T cells and developed a transfer model suitable for defining the contribution of APCs to the development of CD4 T cell memory. Accordingly, naive TCR transgenic T cells were stimulated in vitro with Ag presented by different types of APCs and transferred into MHC class II-deficient mice for parking, and the hosts were later analyzed for long-lived T cell frequency or challenged with suboptimal dose of Ag, and the long-lived cells-driven memory responses were measured. The findings indicate that B cells and CD8α+ dendritic cells sustained elevated frequencies of long-lived T cells that yielded rapid and robust memory responses upon rechallenge with suboptimal dose of Ag. Furthermore, both types of APCs had significant programmed death (PD) ligand 2 expression prior to Ag stimulation, which was maintained at a high level during presentation of Ag to T cells. Blockade of PD ligand 2 interaction with its receptor PD-1 nullified the development of memory responses. These previously unrecognized findings suggest that targeting specific APCs for Ag presentation during vaccination could prove effective against microbial infections.

Presentation of high antigen‐dose by splenic B220lo B cells fosters a feedback loop between T helper type 2 memory and antibody isotype switching

“…C.Cg‐Tg(DO11.10)10Dlo/J and DO11.10/scid mice (H‐2 d ) expressing TCR specific for OVAp were previously described . BALB/c mice (H‐2 d ) were obtained from Harlan Sprague Dawley (Indianapolis, IN).…”

“…To overcome these limitations we began by developing a T‐cell receptor (TCR) transgenic model to increase the frequency of responder T cells and were able to investigate the events controlling effector to memory transition . We then used this ovalbumin (OVA)‐specific DO11.10 TCR transgenic system and adapted it to investigate what the different types of APCs contribute to the development of CD4 T‐cell memory . In this model, DO11.10 CD4 T cells were cultured with OVA peptide (OVAp) ‐loaded APCs in vitro , and the effector T cells were transferred into MHC II‐deficient mice and parked for 2–4 months .…”

“…We then used this ovalbumin (OVA)‐specific DO11.10 TCR transgenic system and adapted it to investigate what the different types of APCs contribute to the development of CD4 T‐cell memory . In this model, DO11.10 CD4 T cells were cultured with OVA peptide (OVAp) ‐loaded APCs in vitro , and the effector T cells were transferred into MHC II‐deficient mice and parked for 2–4 months . Memory T‐cell responses were then analysed before or after challenge with OVAp in vivo .…”

“…Memory T‐cell responses were then analysed before or after challenge with OVAp in vivo . Using this model we have shown that B cells contribute to the generation of CD4 T‐cell memory . As the dose of antigen plays a role in the development of T‐cell memory, we sought to determine whether presentation of increasing doses of antigen by B cells influences the development of T‐cell memory.…”

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

“…The latter population is virtually absent in the CD4 + subset under physiological conditions, but becomes apparent during chronic activation. 23,24 Representative profiles from a CLL patient and a control are reported in Figure 2A. Cumulative data indicated marked differences in the composition of both CD4 + and CD8 + T-cell subsets ( Figure 2B).…”