Clinical Evidence for Deficiencies of TCell Mediated Immunity in the Neonate

Cytomegalovirus (CMV) is a ubiquitous herpes virus that ultimately infects 50-90% of the population. For the vast majority of children and adults, infection, which usually occurs after mucosal contact with bodily secretions, is either asymptomatic or results in a self-limited non-specific viral syndrome characterized by fever, hepatosplenomegaly, leukopenia, and myalgias (Gandhi and Khanna, 2004). During active infection, virus is shed from mucous membranes and is detectable in both urine and saliva. Cell-mediated immunity is essential for control of the disease, and onset of T-cell immunity in results in resolution of viremia, although latent virus can be detected in tissues for life (Harari, 2004). In adults, severe systemic disease is seen only in settings of substantial immunodeficiency, such as concurrent HIV infection or following hematopoietic stem cell transplantation, where infection can result in pneumonitis, hepatitis, retinitis, and other organ dysfunction (Gandhi and Khanna, 2004). Reconstitution of virus-specific CD8+ T cells is sufficient for temporary control of the virus, but CD4 + T-cell immunity appears necessary for long-term immunity (Peggs et al., 2003; Walter et al., 1995) CD4 + T-cell immunity acts, at least in part, by helping maintain functional antigen-specific memory CD8+ T cells, but the nature of this help remains controversial (Bevan, 2004).

In contrast, infection in utero can have dramatic, damaging effects on an otherwise healthy fetus (Brown and Abernathy, 1998; Gandhi and Khanna, 2004). Although the majority of infected infants are asymptomatic, 5-10% will suffer severe neurologic damage including microcephaly, seizures, deafness, and retardation. Additional infants will appear asymptomatic at birth but will progress to have significant hearing loss. Infection acquired after birth is usually asymptomatic, but interestingly both congenital infection and post-natal infection through the pre-school years result in prolonged shedding of the virus, while in adults such continuous shedding after primary CMV infection is limited to approximately 6 months after acquisition. This indicates an inability of the neonatal and infant immune system to control the virus compared to the immunocompetent adult (Stagno, 1983).

Recently we investigated the T-cell responses of infants and children infected with CMV (Tu, 2004). Compared to adults, children demonstrated impaired virus-specific Th1 responses but had relatively normal CD8 + T-cell responses [Figure 6.2 and see (Chen et al., 2004)]. This was true even when primary infections of similar duration in both adults and children were compared. The delay in CD4 + T-cell immunity correlated with prolonged viral shedding in the urine (Tu et al., 2004). Interestingly, CD8+ T-cell immunity seems to be relatively intact even in the setting of congenital CMV infection. Marchant et al. (2003) studied 8 newborns with congenital CMV infection compared to 15 healthy controls. Using tetramer staining

Adult

Child

Whole CMV

1.51

CD4 00

10

1.31

CDS 000

m

Whole CMV

0.66

Whole CMV

0.22

10 100 1000 1000

1.12

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0.6S

B Whole CMV

pp65 peptides

Whole CMV

pp65 peptides

Adult Child P<0.05

Adult Child P<0.05

Adult 10 Child 10 Adult 10 Child 10

Figure 6.2. Impaired CMV-specific CD4 + T-cell responses in children. Blood samples from children and adults with documented CMV infection were stimulated with lysates from CMV infected fibroblasts (whole CMV) or with a set of 138 overlapping peptides derived from the CMV protein pp65 protein (pp65 peptides), and T-cell responses were studied by flow cytometry. (A) Representative results of CMV-specific IFN-y and CD69 expression by CD4 + and CD8+ T cells of a CMV Ab-seropositive adult with presumed chronic infection and a young child with infection of less than 2 years duration. The numbers represent the percentage of CMV-specific or pp65-specific CD4+ or CD8+ T cells as assessed by cells positive for both IFN-y and CD69. (B) Frequency of antigen-specific CD4+ T cells determined flow cytometrically after CMV or pp65 stimulation for a cohort of children with 8-29 months duration of primary infection (child) and a group of adults with presumed chronic CMV infection (adult). (C) CMV-specific CD4 + T cells for children and adults with infections of similar duration (child 1° and adult 1°). Horizontal bars in (B) and (C) indicate group means. Statistical significance was evaluated using the two-tailed, unpaired Student's i-test (from Tu W. et al. Persistent deficiency of CD4 T cell immunity to cytomegalovirus in immunocompetent young children, J. Immunol., 172:3260-67, 2004).

and flow cytometry, they showed that CMV-specific CD8+ T cells could be detected pre-natally and early after birth, and these cells expressed IFN-y, perforin, and granzyme A and could lyse target cells loaded with CMV peptides (Marchant et al., 2003). Although this detailed study does not exclude a potential lag in the onset of CD8 + T-cell immunity in response to congenital CMV infection compared to postnatal infection, the robust nature of the immune response is very striking.

A robust CD8 + but not CD4 + T-cell response to congenital infection is not unique to CMV infection, as a similar pattern of immunity has been observed at birth in cases of congenital infection with Trypanosoma cruzi (Hermann et al., 2002). This congenital infection results in a marked expansion of CD8+ T cells rather than CD4+ T cells, with evidence of oligoclonality of the TCR repertoire indicating that this is the result of antigen-driven expansion. These CD8+ T cells are enriched in markers for activation (HLA-DRhigh), memory (CD45R0high), and end-stage effector cells (CD28-/low), and for cytotoxicity (perforin+). They also have a markedly greater capacity to produce IFN-y and TNF-a than CD8 T+ cells from uninfected newborns. In comparison, the CD4+ T cells in these congenitally infected newborns have undergone much less clonal expansion and acquisition of effector function (Hermann et al., 2002).

Newborns also are highly vulnerable to severe infection with herpes simplex virus (HSV)-1 and -2. Neonatal infection frequently results in death or severe neurological damage, even with the administration of high doses of anti-viral agents, such as acyclovir (Kimberlin, 2004). In contrast, death from disseminated primary HSV infection is distinctly unusual outside the newborn period, except in cases of T-cell immunodeficiency or in recipients of T-cell ablative chemotherapy or immunosuppression (Herget et al., 2005). The increased disease severity in infants correlates with delayed and diminished appearance of HSV-specific Th1 responses, including CD4 + T-cell proliferation, IFN-y and TNF-a secretion, and production of HSV-specific T-cell dependent antibody, compared to adults with primary infection (Burchett et al., 1992; Sullender et al., 1987). It is unknown whether CD8 + T-cell immunity is similarly diminished and delayed. It is also unclear by what age HSV-specific CD4 + T-cell immunity achieves a level equivalent to that of adults.

Developmental limitations in immunity are not restricted to anti-viral immunity. Infections with Toxoplasma gondii, an obligate intracellular protozoan, are common with an overall seroprevalence of 22.5% in the USA (Montoya and Liesenfeld, 2004). In adults, infections most often occur after ingestion of under-cooked meat or food or water contaminated with cat feces, and are usually asymptomatic or result in mild, non-specific symptoms including non-tender lymphadenopathy. In immunocompetent adults, primary toxoplasmosis rarely disseminates to cause other sites of disease, such as chorioretinitis. Cell-mediated immunity driven by Th1 cells is required for containment of the infection, and deficiency in CD4 + T cells, IL-12, CD154, or IFN-y results in increased severity of disease in animal models (Subauste et al., 1999). In contrast to infection in adulthood, congenital infection, which occurs when the organism is transmitted trans-placentally to the fetus during an active maternal infection, can have dire consequences: While the majority of infants are asymptomatic at birth, a large number will progress to develop chorioretinitis and other neurologic complications

(Wilson et al., 1980). In one study, chorioretinitis was already present in 19% of otherwise well appearing infants in whom toxoplasmosis was diagnosed by neonatal screening, and even when treatment was initiated promptly after diagnosis, additional children subsequently developed retinal disease (Guerina et al., 1994).

Similarly, the neonatal immune system has difficulty containing both fungal infections, such as mucocutaneous candidiasis which is common in the first year of life, and intracellular bacterial infections, such as M. tuberculosis. Here the tendency of neonates to develop miliary disease and tuberculous meningitis is paralleled by decreased cell-mediated immunity as assessed by delayed-type hypersensitivity skin tests compared to older children and young adults (Smith et al., 1997). This susceptibility to disseminated tuberculosis appears to persist for at least one year after birth.

Thus, neonates and young infants clinically exhibit increased susceptibility to a number of pathogens that are normally contained by T cell-mediated immunity.

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