Editorial: Memory T Cells: Effectors, Regulators, and Implications for Transplant Tolerance

摘要

The Editorial on the Research Topic Memory T Cells: Effectors, Regulators, and Implications for Transplant Tolerance Memory T-cells respond to previously encountered antigens more rapidly and vigorously than their naive counterparts. They are divided into three subsets: central memory, effector memory, and tissue-resident memory T-cells. They are somewhat resistant to immunosuppressive treatments and are generally believed to be a threat to transplant survival. However, mounting evidence has demonstrated that memory CD8~(+)CD122~(+)T-cells with central memory cell phenotypes (CD45RA~(?)CD44~(high)CD62L~(high)CCR7~(+)) can regulate T-cell homeostasis and suppress both autoimmune and alloimmune responses. Therefore, memory T-cells, especially CD8~(+)CD122~(+)T-cells, may respond as either aggressive memory or regulatory T-cells (Treg). This research topic may shed light on when they act as memory versus Treg cells, and how to target memory T-cells or otherwise utilize memory-like Tregs to promote long-term allograft survival. Memory T-cells are considered to be a major barrier to long-term transplant survival or tolerance ( 1 ). Targeting allospecific T-cell memory appears to be required for transplant tolerance induction. Then, the question is whether blocking conventional T-cell costimulation would inhibit memory T-cell responses. Previous studies have shown that memory T-cells are resistant to CD40/CD154 costimulatory blockade ( 2 , 3 ). It is also generally accepted that B7-CD28 costimulation is not required for memory T-cell activation ( 4 ). They are either less dependent on or totally independent of CD28 costimulation ( 5 , 6 ). Therefore, it is likely that blocking B7–CD28 is insufficient for preventing allograft rejection in the face of memory T-cells. Perhaps that is why a high incidence of acute rejection of renal allografts, despite CTLA4-Ig treatments, has occurred in clinic due to the cross-reactivity of memory T-cells, derived from pathogen-specific immune responses, with an alloantigen ( 7 ). However, recent studies using animal models have shown that optimal elaboration of secondary T-cell responses is dependent on B7–CD28 interactions in the context of anti-infectious immunity ( Ville et al. ). Interestingly, selectively targeting CD28 with FR104 is more potent in suppression of allograft rejection than targeting CD80/86 with CTLA4-Ig ( Ville et al. ), suggesting that selective blockade of CD28 signaling alone presents an advantage of allowing immunoregulatory signals mediated by CTLA4. Furthermore, blocking OX-40 costimulatory signal prolongs secondary heart allograft survival in the presence of CD40/CD40L and LFA-1/ICAM-1 blockade ( 8 ), indicating that additional blockade of OX-40 signaling is required for abrogating memory T cell responses. Memory T-cells can rapidly trigger alloimmune responses ( 9 ). It has been known that early infiltration of CD8~(+)memory T-cells into allografts facilitates allograft rejection and presents a hurdle to achieving long-term allograft survival ( 10 – 12 ). Signaling pathways for memory T-cell migration to an inflamed graft include G protein-coupled chemokine receptor signaling and cognate antigen-engaged TCR signaling as both signals trigger downstream integrin activation ( Zhang and Lakkis ). Interestingly, cognate antigen presence is necessary for driving antigen-specific memory T-cell migration into the peripheral tissue even without acute inflammation ( 13 ). Blocking integrin with anti-LFA-1 or anti-VLA-4 mAb prevents memory T-cell migration to a graft, attenuates alloreactive memory T-cell recall responses, and suppresses allograft rejection ( 14 , 15 ). However, indiscriminately blocking LFA-1, though preventing memory and effector T-cell migration, increases the chance of developing post-transplant EBV-associated lymphoproliferative diseases while targeting VLA-4 may result in reactivation of fatal infections ( 16 ). Therefore, it is important to seek new strategies, instead of the universal blockade of major chemokines, to prevent donor-specific memory T-cell migration without increasing the risk of infections. One potential strategy to do so is to target the inside-out signaling pathway downstream of the TCR but not chemokine receptors ( Zhang and Lakkis ), such as SKAP1, leading to the suppression of antigen-driven but not chemokine-driven memory T-cell migration to a graft. Recently, there has been a renewed interest in immune metabolism in CD8~(+)T-cells. Their proliferation and function require a metabolic adaptation to meet their needs for energy and biosynthesis ( Yap et al. ). Activated CD8~(+)T-cells reprogram their metabolism from OXPHOS to aerobic glycolysis and glutaminolysis ( 17 ), supporting their rapid growth with sufficient energy as well as metabolic intermediates. Since glycolysis and glutaminolysis are two major metabolic pathways that are essential for CD8~(+)effector cell function, blocking metabolic pathways could lead t