An NKG2D-Mediated Human Lymphoid Stress Surveillance Response with High Interindividual Variation

Humans mount lymphocyte stress surveillance responses to MICA, but they are individually tuned to optimal bandwidths. Stress Management The bulk of books dedicated to stress management is a strong indication that people respond differently to stressful situations—from thriving to panic to withdrawal, and everything in between. Yet, relatively little is known about how the human body responds to cellular stress. Cell damage caused by stressors such as chemicals, ultraviolet light, infection, or even tumors can induce the expression of stress antigens, such as MICA, which then are recognized by immune cells. Shafi et al. now show that human immune cells mount stress surveillance responses to MICA and that, as with emotional stress, these responses are individually tuned. MICA is a highly polymorphic stress antigen. Shafi et al. found that polymorphic coding sequences within MICA variants directly affected their expression. Using four MICA variants with different expression levels, the authors found that although lymphocyte stress surveillance responses were observed against MICA in all patients examined, MICA expression levels did not directly correlate with the magnitude of the immune response. Instead, immune cells from some people responded better to higher expression of MICA, whereas others responded better to lower expression. These data suggest that immune surveillance of stress antigens is individually tuned and may help explain patient-specific differences in tumor immune surveillance, transplant rejection, and inflammation. DNA damage or other physicochemical stresses may increase the expression of major histocompatibility complex class I–related stress antigens, which then activate lymphocytes. This lymphoid stress surveillance (LSS) not only can limit tumor formation but may also promote immunopathology. MICA is a highly polymorphic human stress antigen implicated in tumor surveillance, inflammation, and transplant rejection. However, LSS has not been conclusively demonstrated in humans, and the functional role for MICA polymorphisms remains to be established. We show that MICA coding sequence polymorphisms substantially affected RNA and protein expression. All donors tested showed LSS responses of γδ T and natural killer cells, but unexpectedly, each was individually “tuned.” Hence, some responded optimally to highly expressed alleles, whereas others responded better to lower MICA expression, challenging the orthodoxy that higher stress antigen levels promote greater responsiveness. These individual variations in LSS tuning may help explain patient-specific differences in tumor immune surveillance, transplant rejection, and inflammation, as well as provide insight into immune evasion and immunosuppression.