Immunoregulatory pathways following strong inflammatory processes markedly impair CD4+ T cell responses

Abstract

As the research and use of immunotherapies is expanding, isolating ideal combinational strategies has become the next goal for many investigators. Vaccine therapies are also becoming one of the many combinational strategies being utilized in conjunction with immunostimulatory antibodies such as checkpoint blockade or adjuvants to stimulate immune responses. Here we review aspects of the immune responses that remain to be considered for designing future targeted therapies given the recent findings of the role of out of order T cell activation signaling. Specifically, we review some considerations in generating primary T cell responses under conditions of strong immunostimulatory signals based on recent studies completed by our group and others.

Keywords: T cell activation; memory T cell expansion; primary antigen-specific response.

Figure 1.

(T)cell activation patterns. (A) A typical primary T cell activation requires 3 signals to occur in sequence and depends on: 1). antigen recognition by TCR engagement and the strength of the signal received, 2). ligation of co-stimulatory molecules to their ligands and 3). cytokine mediated expansion and differentiation of cells to effector cells. (B) Cytokine exposure alone causes an antigen non-specific “bystander activation” expansion of memory T cells which exhibit broad lytic capabilities in comparison to antigen specfic activated T cells.

Figure 2.

Out of sequence (T)cell activation signaling leads to variable responses. While a typical 3 signal activation results in an antigen specific T cell expansion, a lack of signal 2 can lead to T cell anergy. More recently, it has been shown that signal 3 alone not only causes an expansion of memory T cells into broadly lytic CD8+ T cells, but also causes a transient paralysis of CD4+ T cells thereby suppressing their activation and expansion to memory.