Editorial: 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 autoim-mune 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 …