CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression

Abstract

CD4 + T cell help during the priming of CD8 + T lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. Helped memory CD8 + T cells rapidly expand in response to a secondary antigen exposure, even in the absence of T cell help and, are most efficient in protection against a re-infection. In contrast, helpless memory CTL can mediate effector function, but secondary expansion is reduced. How CD4 + T cells instruct CD8 + memory T cells during priming to undergo efficient secondary expansion has not been resolved in detail. Here, we show that memory CTL after infection with lymphocytic choriomeningitis virus are CD27 high whereas memory CTL primed in the absence of CD4 + T cell have a reduced expression of CD27. Helpless memory CTL produced low amounts of IL-2 and did not efficiently expand after restimulation with peptide in vitro. Blocking experiments with monoclonal antibodies and the use of CD27 -/-memory CTL revealed that CD27 ligation during restimulation increased autocrine IL-2 production and secondary expansion. Therefore, regulating CD27 expression on memory CTL is a novel mechanism how CD4 + T cells control CTL memory.Key words: CD27 Á CD4 T cell help Á Costimulation Á LCMV Á T cell memory IntroductionAfter an acute infection, the initial expansion of CTL is determined by a brief period of antigenic stimulation followed by a contraction to a stable pool of long-lived memory cells [1][2][3]. Memory CTL are characterized by an increased frequency of specific CD8 + T cells with a heightened sensitivity to an antigen that has been encountered previously. The cellular basis influencing memory CTL formation has been the focus of extensive research. Several studies highlighted the importance of CD4 + T cells in the generation of CTL memory [4][5][6]. Memory T lymphocytes that are primed in the absence of CD4 + T cell help have a reduced proliferation capacity. In addition, the production of acute effector cytokines and IL-2 are reduced [7]. "Unhelped" CD8 + T cells die upon in vitro re-activation, due to the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is not expressed by "helped" CD8 + memory T cells [8].The mechanisms how CD4 + T cell help drives CD8 + T cell memory has not been resolved in detail. Mice deficient for CD40L have CD8 + memory T cells with reduced function. The CD40-CD40L interaction may be involved in the generation of CTL memory via two mechanisms. First, CD4 + T cells expressing CD40L activate APC through CD40 and these "licensed" APC are then able to drive CD8 + T cell responses [9][10][11]. Secondly, CD4 + T cells expressing CD40L may directly deliver help to CD8 + T cells [7]. Besides the CD40-CD40L interaction, other receptor-ligand interactions such as the CD27-CD70 interaction may be important for generating functional CD8 + memory T cells [12]. In addition, soluble signals may be involved in CD8 + T cell formation. It has been reported that IL-4-secreting CD4 + T cells are involved in the formation of memo...

CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production

“…Other researchers have also found a link between CD27 and IL-2 in memory CD8 + T cell programming. They have demonstrated that CD4 + T cell help is required for maintenance of CD27 expression on memory CD8 + T cells, which facilitated IL-2 expression upon secondary expansion (44).…”

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

“…Memory CD8 T cells, generated in the presence of CD4 help, have been reported to express high levels of CD27, and the ligation of CD27 during restimulation has been shown to increase secondary expansion and autocrine IL-2 production. 39 Whatever the reason for these differences, the absolute requirement for CD4 help and the involvement of CD40 and CD40L in producing an optimal H60-specific CD8 response is preserved between the primary and memory responses. It is well known that CD4 help during the primary response gives CD8 T cells a high capacity for expansion upon rechallenge.…”

Humoral and cellular immune responses to influenza vaccination in children with cancer receiving chemotherapy

“…Certain studies have suggested that cellular immunity to an influenza vaccine is a useful predictor of protection against disease in the elderly (20). The cellular immune response to an influenza vaccine has been described as the expansion of CD8 + and CD4 + T lymphocytes with surface markers that classify them as effector or memory T cells based on the surface markers CD62L and CD45RA (21)(22)(23)(24); other molecules, including CD27, are costimulatory and indicate activation (25). These surface markers have yet to be characterized in children with cancer who are receiving chemotherapy and who have been immunized with an influenza vaccine.…”