Development of CTL memory despite arrested clonal expansion

Abstract

Activation of a cytotoxic T lymphocyte (CTL) response in an antigen-exposed lymph node involves a great diversity of encounters between naive CTL and APC that differ in both duration and quality. This broad spectrum of priming events instigates a complex blend of CTL developmental pathways. Using an experimental system that allows tight control over CTL priming, we have singled out defined priming events and analyzed the impact of the resulting instructional program on the effector and memory phases of the CTL response. As expected, prolonged antigenic stimulation induces potent CTL expansion, effector function and CTL memory. In contrast, CTL that have received suboptimal stimulation fail to undergo extensive expansion. Nevertheless these arrested CTL persist long term and acquire memory function. Thus, our data demonstrate that CTL memory can develop as a result of a suboptimal stimulation that causes arrested clonal expansion. Key words: CD8 T cells Á Cell differentiation Á Cellular proliferation Á Memory cells IntroductionT cells protect the health of an organism by mounting a wellorchestrated immune response consisting of proliferation, effector cell differentiation, contraction and memory formation. These aspects of the T cell response are programmed during the initial contact of naive T cells with antigen-presenting cells (APC) [1][2][3][4]. The strength of the signal that is delivered during primary stimulation determines the quality of the T cell differentiation program [5,6]. The interrelationship between the T cell types that represent the different stages of the immune response, the naive T cells, effector T cells and memory T cells, is still a matter of debate. Some studies support a linear differentiation model wherein naive T cells first develop into effector cells and thereafter into memory cells [7][8][9]. Other studies suggest (partially) parallel pathways of effector and memory T cell generation [10, 11].As a consequence of the primary T cell response, different subsets of memory T cells can emerge, in particular the central memory (Tcm) and effector memory (Tem) T cells. Although the exact phenotypic definitions of the two subsets differ slightly between mouse and human T cells and among different research groups, it is generally accepted that Tcm cells express CD62L and therefore preferentially localize in lymphoid tissues, whereas Tem cells lack these features and therefore mainly reside in the blood and non-lymphoid tissues (reviewed in [12,13]). The two memory subsets also complement each other functionally, in that Tem cells exhibit immediate effector function while Tcm cells cause expansion of responding cells through extensive cell division. The lineage relationship between the subsets of memory cells is still unclear, calling for further study on the factors deciding between the formation of Tcm versus Tem cells [14][15][16][17]. A recent study has shed some light on this issue by showing that high T cell precursor frequencies favor Tcm cell formation while low precursor frequencies p...

Separate Roles for Antigen Recognition and Lymph Node Inflammation in CD8+ Memory T Cell Formation

“…Prior work had demonstrated that a 20-h in vitro encounter with these APCs empowered naive OT-I cells to vigorously proliferate in vivo upon transfer to naive syngeneic recipient (15). Furthermore, these T cells were shown to develop into long-lived memory cells, capable of clonal expansion and protective effector function in response to secondary Ag encounter (16). Importantly, progression of the 20 h primed OT-I T cells through primary expansion, contraction, and memory phases required neither in vivo exposure to Ag nor the context of an inflamed, congested lymph node.…”

Naloxone/alum mixture a potent adjuvant for HIV-1 vaccine: induction of cellular and poly-isotypic humoral immune responses

“…20 In fact, T cells protect the health of an organism by mounting a well-orchestrated immune response consisting of proliferation effector cell differentiation, contraction and induction of cytotoxic T lymphocytes that kill viral infected cells. 21 In general, effector CD8+ T cells control infection through cytotoxic activity and the secretion of IFN-γ and TNF-α. 22 Moreover, CTL plays a major role in adaptive immunity to viral infections such as HIV-1.…”

Neoantigen Expression in Steady-State Langerhans Cells Induces CTL Tolerance

“…CTLs can persist for a long time and acquire memory function even under suboptimal stimulation conditions (42). Similarly, in our LCre-GFPOA mice, antigen presentation by resting LCs without additional co-stimulation was sufficient to prime endogenous CTL, and to develop effector function.…”