The roles of the CD4+ (T helper) lymphocyte in regulating the murine cytotoxic T lymphocyte reponse to herpes simplex virus type 1

This communication presents an approach for identifying the requirement of CD4+ T lymphocytes in the induction and expansion of HSV-1 specific CTL in vivo. Rat monoclonal antibodies were used to selectively deplete mice of CD8+ and CD4+ T cellsin vivo in order to assess the requirements of CD4+ T lymphocytes in the induction and expansion of HSV-1 specific CTL. These antibodies produced greater than 95% depletion of their respective T cell subsets as determined by flow cytometry. Functional depletion of CD4+ cells was evident by supressed antibody response towards Rabbit IgG and suppressed neutralizing antibody response to HSV-1,both T-dependent antigens. Additional functional evidence was shown by a reduction of HSV-1 specific delayed-type hypersensitivity. CD4+ deficient mice could generate a memory HSV-1 -specific CTL response, yet acutely infected mice could not generate HSV-specific CTLs. This response was strain specific.

In addition to the aforementioned studies, a limiting dilution microculture system was utilized to calculate the frequencies of CTL-p reactive against HSV-1 in CD4+depleted and non-depleted mice. Tazwell analysis (160) demonstrated that the estimated frequency of HSV-1 reactive cells in the lymph nodes of non-depleted immune mice was 1/6063, while in immune, CD4+ depleted mice the frequency was 1/9162. In addition to this, lymph node cells from these mice, when restimulated in vitro with HSV-1 infected irradiated splenocytes, demonstrated CTL-p frequencies of 1/2654 and 1 /1177 respectively. These observations clearly demonstrate that CD8+ CTL-ps can be IV induced in a CD4+-deficient environment. However, there may be different requirements in both systems as to the expansion and differentiation of these cells. The results suggest that the expansion of CTL-p to their aggressor status in the primary HSV-1 -specific CTL response in CD4+ deficient animals is dependent upon soluble growth factors, these factors probably being secreted by a Th cell. The implications of these observations respective to the induction and subsequent expansion of HSV-1 -specific CD8+CTLs are discussed.