Duration of Antigen Availability Influences the Expansion and Memory Differentiation of T Cells

Abstract

The initial engagement of the T cell receptor (TCR) through interaction with cognate peptide-MHC is a requisite for T cell activation and confers antigen specificity. While this is a key event in T cell activation, the duration of these interactions may affect the proliferative capacity and differentiation of the activated cells. Here, we developed a system to evaluate the temporal requirements for antigenic stimulation during an immune response, in vivo. Using antibodies that target specific antigens in the context of MHC, we were able to manipulate the duration of antigen availability to both CD4 and CD8 T cells during an active infection. During the primary immune response, the magnitude of the CD4 and CD8 T cell response was dependent on the duration of antigen availability. Both CD4 and CD8 T cells required sustained antigenic stimulation for maximal expansion. Memory cell differentiation was also dependent on the duration of antigen exposure, albeit to a lesser extent. However, memory development did not correlate with the magnitude of the primary response, suggesting that the requirements for continued expansion of T cells and memory differentiation are distinct. Finally, a shortened period of antigen exposure was sufficient to achieve optimal expansion of both CD4 and CD8 T cells during a recall response. It was also revealed that limiting exposure to antigen late during the response may enhance the CD4 T cell memory pool. Collectively, these data indicated that antigen remains a critical component of the T cell response after the initial APC-T cell interaction.

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

“…However, there is also data that CD8 + T cell expansion is correlated with the continued duration of TCR stimulation in the context of both infections and sterile vaccinations (13)(14)(15)(16)(17)(18)(19)(20)(21). The reason for this discrepancy is currently unclear and cannot be explained by differences of protocol, experimental systems or availability of help or inflammation.…”

“…Two studies supplied evidence for the notion that TCRtriggered CD4 + T cells keep proliferating in the absence of Ag and cytokines (22,23), whereas others did not support such an early-programming scenario but rather supplied evidence for the importance of maintained TCR signals (24)(25)(26)(27). Most of the experiments done in vivo supported the Ag dependency of CD4 + T cells throughout the expansion phase (8,13,(28)(29)(30)(31)(32)(33).…”

“…It has been noted in many infections of mice and humans that the magnitude of the CD8 + T cell response is larger than that of CD4 + T cells and an intrinsic difference between the subsets has been invoked (35,36). However, whether Ag requirements in the expansion phase differ between CD4 + and CD8 + T cells has been asked in few studies that came to different conclusions (8,13,32). Thus, we examined the Ag dependency of CD4 + and CD8 + T cell proliferation side by side in a way that excludes cross-talk between the subsets.…”

Beyond antigens and adjuvants: formulating future vaccines

“…Persistent antigen/inflammation exposure in draining LNs over periods of at least several days can be important for maximizing the immune response, enhancing the differentiation of follicular Th cells (106,107), enhancing GC induction (35), and producing an optimal cytokine milieu (108). The duration and magnitude of antigen and adjuvant exposure during priming of naive lymphocytes or boosting of memory cells is known to play a significant role in determining the degree of clonal expansion (109)(110)(111), fate decisions between different functional phenotypes (Th subsets or plasma cells versus memory cell differentiation of B cells; refs. 106,112), and the quality of memory established (113,114).…”

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

“…More specifically, memory CD4 + T cells promote viral clearance through a variety of synergizing mechanisms, including Thmediated perforin cytotoxicity and the enhancement of B-cell and CD8 + T-cell responses (8)(9)(10). T-cell priming by dendritic cells (DCs) is a pivotal process for the acquisition of T-cell memory that largely influences the strength and efficiency of recall immune responses after subsequent virus infections (11)(12)(13). Several studies have shown that hRSV infects human and mouse DCs, impairing their capacity to activate both naïve (14) and antigen-experienced CD4 + T cells (15,16).…”